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1.	Andresen Bergström, Moa, 1978, et al. (författare) Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation. 2006 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 19:6, s. 760-9 Tidskriftsartikel (refereegranskat)abstract There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.
2.	Andresen Bergström, Moa, 1978, et al. (författare) Metabolic epoxidation of an alpha,beta-unsaturated oxime generates sensitizers of extreme potency. Are nitroso intermediates responsible? 2007 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 20:6, s. 927-936 Tidskriftsartikel (refereegranskat)abstract Metabolic activation of inherently nonprotein-reactive compounds (prohaptens) in the skin can lead to development of contact allergy, a chronic skin disease. The prohapten hypothesis has existed for more than 20 years; yet, detailed knowledge regarding the mechanisms of activation as well as what structural moieties can be transformed to protein-reactive sensitizers is still limited. Today, the consideration of cutaneous bioactivation is important when developing nonanimal-based assays for prediction of contact allergenic activity, as only methods that include skin metabolism are able to detect prohaptens as sensitizers. We have studied the mechanism of activation of the prohapten carvoxime (1), a strongly sensitizing but in itself poorly protein-reactive alpha,beta-unsaturated oxime. alpha,beta-Unsaturated oximes represent a novel class of prohaptens, which previously have never been investigated for potential metabolic activation. To identify reactive metabolites formed from (1), liver microsomal incubations in the presence of glutathione were carried out. Putative reactive metabolites were synthesized, and their allergenic activity, chemical reactivity toward nucleophiles, and ability to elicit a contact allergenic response in animals induced with 1 were assessed. We found that 1 is metabolically activated by epoxidation of the allylic carbon-carbon double bond. The alpha,beta-epoxy oxime metabolites were found to be sensitizers of extreme potency in the local lymph node assay and highly reactive toward nucleophilic amino acids and a model peptide. One of the two diastereomeric epoxy metabolites also elicited an allergic reaction in mice sensitized to 1, in the mouse ear swelling test. Furthermore, this study presents strong indications that the basis of the high reactivity and sensitizing capacity observed for the alpha,beta-unsaturated oximes is related to their ability to form highly reactive nitroso intermediates by tautomerization. To our knowledge, the formation of nitrosoalkenes by oxidative metabolism of alpha,beta-unsaturated oximes has not been shown so far.
3.	Bauer, Brigitte, 1978, et al. (författare) Modification and expulsion of keratins by human epidermal keratinocytes upon hapten exposure in vitro. 2011 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:5, s. 737-43 Tidskriftsartikel (refereegranskat)abstract Allergic contact dermatitis is the most prevalent form of human immunotoxicity. It is caused by reactive low molecular weight chemicals, that is, haptens, coming in contact with the skin where hapten-peptide complexes are formed, activating the immune system. By using sensitizing fluorescent thiol-reactive haptens, that is, bromobimanes, we show how keratinocytes respond to hapten exposure in vitro and reveal, for the first time in a living system, an exact site of haptenation. Rapid internalization and reaction of haptens with keratin filaments were visualized. Subsequently, keratinocytes respond in vitro to hapten exposure by release of membrane blebs, which contain haptenated keratins 5 and 14. Particularly, cysteine 54 of K5 was found to be a specific target. A mechanism is proposed where neoepitopes, otherwise hidden from the immune system, are released after hapten exposure via keratinocyte blebbing. The observed expulsion of modified keratins by keratinocytes in vitro might play a role during hapten sensitization in vivo and should be subject to further investigations.
4.	Bell, Catherine C., et al. (författare) T-cells from HLA-B57 : 01+ human subjects are activated with abacavir through two independent pathways and induce cell death by multiple mechanisms 2013 Ingår i:* Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 26:5, s. 759-766 Tidskriftsartikel (refereegranskat)abstract Susceptibility to abacavir hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B57:01. HLA-B57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between abacavir accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to abacavir. Certain clones were activated with abacavir in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with abacavir, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of abacavir in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular abacavir was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by abacavir through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, abacavir seemingly participates in the MHC T-cell receptor binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of abacavir exposure, but not abacavir itself.
5.	Busquets, Rosa, et al. (författare) Biomonitoring of Dietary Heterocyclic Amines and Metabolites in Urine by Liquid Phase Microextraction: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a Possible Biomarker of Exposure to Dietary PhIP 2013 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 26:2, s. 233-240 Tidskriftsartikel (refereegranskat)abstract Heterocyclic amines (HCAs) are mutagenic/carcinogenic compounds formed at ng/g levels during frying meat or fish. The effect of the normal intake of dietary HCAs in humans and their involvement in the etiology of cancer are currently unknown. In this work, a new extraction method, liquid phase microextraction (LPME) with hollow fibers, and LC-MS/MS have been used for the first time to determine HCAs and metabolites in nonspiked human urine following a single meal of chicken cooked at 180 degrees C for 6 min. The total intake of HCAs was estimated to be 6 mu g, of which 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) accounted for about 1 mu g. The concentrations of PhIP in nonhydrolyzed urine samples ranged from 11.7 to 59.4 pg/g. The total amount of PhIP in urine ranged between 9.3 and 21.1 ng, which corresponds to 0.91-2.1% of the ingested PhIP. In addition, the urine levels of 4'-OH-PhIP (2-amino-1-methyl-6-(4'-hydroxy)phenylimidazo[4,5-b]pyridine) and 5-OH-PhIP (2-amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine) also showed a narrow variation between the samples. The analysis of urine samples after acid hydrolysis did not give additional information but showed a notable increase in norharman in some cases. The obtained results suggest PhIP in urine as a possible biomarker of exposure to HCAs and the LPME and LC-MS/MS method as an appropriate strategy to biomonitor HCAs in urine.
6.	Carlsson, Henrik, et al. (författare) Adductomic Screening of Hemoglobin Adducts and Monitoring of Micronuclei in School-Age Children 2017 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 30:5, s. 1157-1167 Tidskriftsartikel (refereegranskat)abstract Electrophilic compounds/metabolites present in humans, originating from endogenous processes or exogenous exposure, pose a risk to health effects through their reactions with nucleophilic sites in proteins and DNA, forming adducts. Adductomic approaches are developed to screen for adducts to biomacromolecules in vivo by mass spectrometry (MS), with the aim to detect adducts corresponding to unknown exposures from electrophiles. In the present study, adductomic screening was performed using blood samples from healthy children about 12 years old (n = 51). The frequencies of micronuclei (MN) in erythrocytes in peripheral blood were monitored as a measure of genotoxic effect/genotoxic exposure. The applied adductomic approach has been reported earlier by us and is based on analysis of N-terminal valine adducts in hemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). High resolution MS was introduced for refined screening of previously unknown N-terminal Hb adducts. Measured adduct levels were compared with MN frequencies using multivariate data analysis. In the 51 individuals, a total of 24 adducts (whereof 12 were previously identified) were observed and their levels quantified. Relatively large interindividual variations in adduct levels were observed. The data analysis (with partial least-squares regression) showed that as much as 60% of the MN variation could be explained by the adduct levels. This study, for the first time, applies the combination of these sensitive methods to measure the internal dose of potentially genotoxic chemicals and genotoxic effects, respectively. The results indicate that this is a valuable approach for the characterization of exposure to chemical risk factors for the genotoxic effects present in individuals of the general population.
7.	Carlsson, Henrik, et al. (författare) Characterization of a Hemoglobin Adduct from Ethyl Vinyl Ketone Detected in Human Blood Samples 2015 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 28:11, s. 2120-2129 Tidskriftsartikel (refereegranskat)abstract Electrophiles have the ability to form adducts to nudeophilic sites in proteins and DNA. Internal exposure to such compounds thus constitutes a risk for toxic effects. Screening of adducts using mass spectrometric methods by adductomic approaches offers possibilities to detect unknown electrophiles present in tissues. Previously, we employed untargeted adductomics to detect 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. This article describes the characterization of one of these adducts, which was identified as the adduct from ethyl vinyl ketone (EVK). The mean adduct level was 40 +/- 12 pmol/g Hb in 12 human blood samples; adduct levels from acrylamide (AA) and methyl vinyl ketone (MVK) were quantified for comparison. Using L-valine p-nitroanilide (Val-pNA), introduced as a model of the N-terminal valine, the rate of formation of the EVK adduct was studied, and the rate constant determined to 200 M(-1)h(-1) at 37 degrees C. In blood, the reaction rate was too fast to be feasibly measured, EVK showing a half-life <1 min. Parallel experiments with AA and MVK showed that the two vinyl ketones react approximately 2 x 10(3) times faster than AA. The EVK-Hb adduct was found to be unstable, with a half-life of 7.6 h. From the mean adduct level measured in human blood, a daily dose (area under the concentration-time-curve, AUC) of 7 nMh EVK was estimated. The AUC of AA from intake via food is about 20 times higher. EVK is naturally present in a wide range of foods and is also used as a food additive. Most probably, naturally formed EVK is a major source to observed adducts. Evaluation of available toxicological data and information on occurrence of EVK indicate that further studies of EVK are motivated. This study illustrates a quantitative strategy in the initial evaluation of the significance of an adduct detected through adduct screening.
8.	Carlsson, Henrik, et al. (författare) LC–MS/MS Screening Strategy for Unknown Adducts to N-Terminal Valine in Hemoglobin Applied to Smokers and Nonsmokers 2014 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:12, s. 2062-2070 Tidskriftsartikel (refereegranskat)abstract Electrophilically reactive compounds have the ability to form adducts with nucleophilic sites in DNA and proteins, constituting a risk for toxic effects. Mass spectrometric detection of adducts to N-terminal valine in hemoglobin (Hb) after detachment by modified Edman degradation procedures is one approach for in vivo monitoring of exposure to electrophilic compounds/metabolites. So far, applications have been limited to one or a few selected reactive species, such as acrylamide and its metabolite glycidamide. This article presents a novel screening strategy for unknown Hb adducts to be used as a basis for an adductomic approach. The method is based on a modified Edman procedure, FIRE, specifically developed for LC-MS/MS analysis of N-terminal valine adducts in Hb detached as fluorescein thiohydantoin (FTH) derivatives. The aim is to detect and identify a priori unknown Hb adducts in human blood samples. Screening of valine adducts was performed by stepwise scanning of precursor ions in small mass increments, monitoring four fragments common for the FTH derivative of valine with different N-substitutions in the multiple-reaction mode, covering a mass range of 135 Da (m/z 503-638). Samples from six smokers and six nonsmokers were analyzed. Control experiments were performed to compare these results with known adducts and to check for artifactual formation of adducts. In all samples of smokers and nonsmokers, seven adducts were identified, of which six have previously been studied. Nineteen unknown adducts were observed, and 14 of those exhibited fragmentation patterns similar to earlier studied FTH derivatives of adducts to valine. Identification of the unknown adducts will be the focus of future work. The presented methodology is a promising screening tool using Hb adducts to indicate exposure to potentially toxic electrophilic compounds and metabolites.
9.	Chavan, Swapnil, et al. (författare) Predicting Chemical-Induced Liver Toxicity Using High-Content Imaging Phenotypes and Chemical Descriptors : A Random Forest Approach 2020 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 33:9, s. 2261-2275 Tidskriftsartikel (refereegranskat)abstract Hepatotoxicity is a major reason for the withdrawal or discontinuation of drugs from clinical trials. Thus, better tools are needed to filter potential hepatotoxic drugs early in drug discovery. Our study demonstrates utilization of HCI phenotypes, chemical descriptors, and both combined (hybrid) descriptors to construct random forest classifiers (RFCs) for the prediction of hepatotoxicity. HCI data published by Broad Institute provided HCI phenotypes for about 30 000 samples in multiple replicates. Phenotypes belonging to 346 chemicals, which were tested in up to eight replicates, were chosen as a basis for our analysis. We then constructed individual RFC models for HCI phenotypes, chemical descriptors, and hybrid (chemical and HCI) descriptors. The model that was constructed using selective hybrid descriptors showed high predictive performance with 5-fold cross validation (CV) balanced accuracy (BA) at 0.71, whereas within the given applicability domain (AD), independent test set and external test set prediction BAs were equal to 0.61 and 0.60, respectively. The model constructed using chemical descriptors showed a similar predictive performance with a 5-fold CV BA equal to 0.66, a test set prediction BA within the AD equal to 0.56, and an external test set prediction BA within the AD equal to 0.50. In conclusion, the hybrid and chemical descriptor-based models presented here should be considered as a new tool for filtering hepatotoxic molecules during compound prioritization in drug discovery.
10.	Cho, KB, et al. (författare) Conformations of benzene- and dibenzo[a,l]pyrene diol epoxides studied by density functional theory: ground states, transition states, dynamics, and solvent effects 2003 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 16:5, s. 590-597 Tidskriftsartikel (refereegranskat)
11.	Davies, Ronnie, et al. (författare) A New General Pathway for Synthesis of Reference Compounds of N-Terminal Valine-Isocyanate Adducts 2010 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 23:3, s. 540-546 Tidskriftsartikel (refereegranskat)abstract Adducts to Hb could be used as biomarkers to monitor exposure to isocyanates. Particularly useful is the measurement of carbamoylation of N-terminal valines in Hb, after detachment as hydantoins. The synthesis of references from the reactive isocyanates, especially diisocyanates, has been problematic due to side reactions and polymerization of the isocyanate starting material. A simpler, safer, and more general method for the synthesis of valine adducts of isocyanates has been developed using N-[(4-nitrophenyl)-carbamate]valine methylamide (NPCVMA) as the key precursor to adducts of various mono- and diisocyanates of interest. By reacting NPCVMA with a range of isocyanate-related amines, carbamoylated valines are formed without the use of the reactive isocyanates. The carbamoylated products synthesized here were cyclized with good yields of the formed hydantoins. The carbamoylated derivative from phenyl isocyanate also showed quantitative yield in a test with cyclization tinder the conditions used in blood. This new pathway for the preparation of N-carbamoylated model compounds overcomes the above-mentioned problems in the synthesis and is a general and simplified approach, which could make such reference compounds of adducts to N-terminal valine from isocyanates accessible for biomonitoring purposes. The synthesized hydantoins corresponding to adducts from isocyanic acid, methyl isocyanate, phenyl isocyanate, and 2,6-toluene diisocyanate were characterized by LC-MS analysis. The background level of the hydantoin from isocyanic acid in human blood was analyzed with the LC-MS conditions developed.
12.	Degner, Amanda, et al. (författare) Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood 2018 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 31:12, s. 1305-1314 Tidskriftsartikel (refereegranskat)abstract Humans are exposed to a wide range of electrophilic compounds present in our diet and environment or formed endogenously as part of normal physiological processes. These electrophiles can modify nucleophilic sites of proteins and DNA to form covalent adducts. Recently, powerful untargeted adductomic approaches have been developed for systematic screening of these adducts in human blood. Our earlier untargeted adductomics study detected 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. We now describe a full characterization of one of these adducts, which corresponds to the addition of a 4-hydroxybenzyl (4-OHBn) group to N-terminal valine in Hb to form N(4-hydroxybenzyl)valine (4-OHBn-Val). The adduct structure was determined by comparison of its accurate mass, HPLC retention time, and MS/MS fragmentation to that of authentic standards prepared by chemical synthesis. Average 4-OHBn-Val adduct concentrations in 12 human blood samples were estimated to 380 +/- 160 pmol/g Hb. Two possible routes of 4-OHBnVal adduct formation are proposed using two different precursor electrophiles: 4-quinone methide (4-QM) and 4-hydroxybenzaldehyde (4-OHBA). We found that 4-QM reacts rapidly with valine to form the 4-OHBn-Val adduct; however, the quinone methide is unstable under physiological conditions due to hydrolysis. It was shown that 4-OHBA forms reversible Schiff base adducts with valine, which can be stabilized via reduction in blood generating the 4-OHBn-Val adduct. In addition, trace amounts of isomeric 2-hydroxybenzyl-valine (2-OHBn-Val) adducts were detected in 12 human blood samples (estimated mean adduct level, 5.0 +/- 1.4 pmol/g Hb). Further studies are needed to quantify the contributions from identified possible precursor electrophiles to the observed hydroxybenzyl adducts in humans.
13.	Delaine, Tamara, 1981, et al. (författare) Correction to skin sensitization of epoxyaldehydes: importance of conjugation. 2014 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 27:2 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
14.	Delaine, Tamara, 1981, et al. (författare) Epoxyalcohols: bioactivation and conjugation required for skin sensitization. 2014 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 27:10, s. 1860-70 Tidskriftsartikel (refereegranskat)abstract Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.
15.	Delaine, Tamara, 1981, et al. (författare) Skin Sensitization of Epoxyaldehydes: Importance of Conjugation. 2013 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 26:5, s. 674-684 Tidskriftsartikel (refereegranskat)abstract Structure-activity relationship (SAR) models are important tools for predicting the skin sensitization potential of new compounds without animal testing. In compounds possessing a structural alert (aldehyde) and an activation alert (double bond), it is important to consider bioactivation/autoxidation (e.g., epoxidation). In the present study, we have explored a series of aldehydes with regard to contact allergy. The chemical reactivity of these 6 aldehydes toward a model hexapeptide was investigated, and their skin sensitization potencies were evaluated using the local lymph node assay (LLNA). Overall, we observed a similar trend for the in vitro reactivity and the in vivo sensitization potency for the structural analogues in this study. The highly reactive conjugated aldehydes (α,β-unsaturated aldehydes and 2,3-epoxyaldehydes) are sensitizing moieties, while nonconjugated aldehydes and nonterminal aliphatic epoxides show low reactivity and low sensitization potency. Our data show the importance of not only double bond conjugation to aldehyde but also epoxide-aldehyde conjugation. The observations indicate that the formation of nonconjugated epoxides by bioactivation or autoxidation is not sufficient to significantly increase the sensitization potency of weakly sensitizing parent compounds.
16.	Delaine, Tamara, 1981, et al. (författare) Structure-Activity Relationship between the in Vivo Skin Sensitizing Potency of Analogues of Phenyl Glycidyl Ether and the Induction of Nrf2-Dependent Luciferase Activity in the KeratinoSens in Vitro Assay. 2011 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:8, s. 1312-8 Tidskriftsartikel (refereegranskat)abstract Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain.
17.	Dreij, K, et al. (författare) Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides 2002 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 15, s. 825-831 Tidskriftsartikel (refereegranskat)
18.	Dreij, K, et al. (författare) Differential removal of DNA adducts derived from anti-diol epoxides of dibenzo[a,l]pyrene and benzo[a]pyrene in human cells 2005 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 18:4, s. 655-664 Tidskriftsartikel (refereegranskat)
19.	Eide, I, et al. (författare) Comparison of (32)P-postlabeling and high-resolution GC/MS in quantifying N7-(2-Hydroxyethyl)guanine adducts 1999 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 12:10, s. 979-984 Tidskriftsartikel (refereegranskat)
20.	Elmsjo, Albert, et al. (författare) Post-Mortem Metabolomics: A Novel Approach in Clinical Biomarker Discovery and a Potential Tool in Death Investigations 2021 Ingår i: Chemical Research in Toxicology. - : AMER CHEMICAL SOC. - 0893-228X .- 1520-5010. ; 34:6, s. 1496-1502 Tidskriftsartikel (refereegranskat)abstract Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molecules (so-called metabolites) in a biological system. At the time of death, the level and type of metabolites present will most likely reflect the events leading up to death. In this proof of concept study, we investigated the potential of post-mortem metabolomics by identifying post-mortem biomarkers, correlated these identified biomarkers with those reported in clinical metabolomics studies, and finally validated the models predictability of unknown autopsy cases. In this post-mortem metabolomics setting, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 404 post-mortem samples, including pneumonia cases and control cases, were processed using XCMS (R). Potential biomarkers were evaluated using principal component analysis and orthogonal partial least squares-discriminant analysis. Biomarkers were putatively annotated using an in-house database and the online databases METLIN and HMDB. The results showed that clear group separation was observed between pneumonia cases and control cases. The metabolites responsible for group separation belonged to a broad set of biological classes, such as amino acids, carnitines, lipids, nicotinamides, nucleotides, and steroids. Many of these metabolites have been reported as important in clinical manifestation of pneumonia. For the unknown autopsy cases, the sensitivity and specificity were 86 and 84%, respectively. This study successfully investigated the robustness and usability of post-mortem metabolomics in death investigations. The identified post-mortem biomarkers correlated well with biomarkers reported and identified through clinical research.
21.	Fred, Charlotta, et al. (författare) Hemoglobin adduct levels in rat and mouse treated with 1,2:3,4-diepoxybutane 2004 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 17:6, s. 785-794 Tidskriftsartikel (refereegranskat)abstract For cancer risk assessment of 1,3-butadiene from rodent cancer test data, the in vivo doses of formed 1,2:3,4-diepoxybutane (DEB) should be known. In vivo doses of DEB were measured through a specific reaction product with hemoglobin (Hb), a ring-closed adduct, N,N-(2,3-dihydroxy-1,4-butadiyl)valine (Pyr-Val), to N-terminal valines. An analytical method based on tryptic digestion of Hb and quantification of Pyr-modified heptapeptides by LC-MS/MS has been further developed and applied in vivo to DEB-treated rats. Furthermore, N-(2,3,4-trihydroxybutyl)valine adducts (THB-Val) to the N-terminal valine in Hb were measured in rats and mice treated with DEB and in a complementary experiment with 1,2-epoxy-3,4-butanediol (EBdiol), using a modified Edman degradation method and GC-MS/MS. In vitro reactions of hemolysate with DEB and EBdiol were used to measure reaction rates for adduct formation needed for calculation of doses and rates elimination in vivo. The results showed that the level of the Pyr-Val adduct per administered dose of DEB was approximately the same in rats as had earlier been observed in mice [Kautiainen et al. (2000) Rapid Commun. Mass Spectrom. 14, 1848−1853]. Levels of the THB-Val adduct after DEB treatment were 3−4 times higher in rat than in mouse, probably reflecting an enhanced hydrolysis of DEB to EBdiol catalyzed by epoxide hydrolase. After EBdiol treatment, the THB-Val adduct levels were about the same in rat and mouse. Calculations from in vitro data show that the Pyr-Val adduct is a relevant monitor for the in vivo dose of DEB and that THB-Val primarily reflects doses to EBdiol. The calculated rates of formation of adducts and rates of elimination agree with expectations. Procedures for quantification of Hb adducts as modified peptides as well as preparation and characterization of peptide standards have been evaluated.
22.	Geib, T, et al. (författare) Investigation of Clozapine and Olanzapine Reactive Metabolite Formation and Protein Binding by Liquid Chromatography-Tandem Mass Spectrometry 2020 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 33:9, s. 2420-2431 Tidskriftsartikel (refereegranskat)
23.	Ghorbanzadeh, Mehdi, et al. (författare) In vitro and in silico derived relative effect potencies of Ah-Receptor-mediated effects by PCDD/Fs and PCBs in rat, mouse, and guinea pig CALUX Cell Lines 2014 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:7, s. 1120-1132 Tidskriftsartikel (refereegranskat)abstract For a better understanding of species-specific relative effect potencies (REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs were calculated using chemical-activated luciferase gene expression assays (CALUX) derived from guinea pig, rat, and mouse cell lines. Almost all 20 congeners tested in the rodent cell lines were partial agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For this reason, REPs were calculated for each congener using concentrations at which 20% of the maximal TCDD response was reached,(REP20TCDD). REP20TCDD values obtained for PCDD/Fs were comparable with their toxic equivalency factors assigned by the World Health Organization (WHO-TEF), while those for PCBs were in general lower than the WHO-TEF values. Moreover, the guinea pig cell line was the most sensitive as indicated by the 20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea pig, rat, and mouse cells, respectively. A similar response pattern was observed using multivariate statistical analysis between the three CALLTX assays and the WHO-TEFs. The mouse assay showed minor deviation due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran was more than two times more potent in the mouse assay as compared with that of rat and guinea pig cells, while measured REP20TCDD for PCB126 was lower in mouse cells (0.05) as compared with that of the guinea pig (0.2) and rat (0.07). In order to provide REP20TCDD values for all WHO-TEF assigned compounds, quantitative structure activity relationship (QSAR) models were developed. The QSAR models showed that specific electronic properties and molecular surface characteristics play important roles in the AhR-mediated response. In silica derived REP20TCDD values were generally consistent with the WHO-TEFs with a few exceptions. The QSAR models indicated that, e.g., 1,2,3,7,8-pentachlorodibenzofuran and 1,2,3,7,8,9-hexachlorodibenzofuran were more potent than given by their assigned WHO-TEF values, and the non-ortho PCB 81 was predicted, based on the guinea-pig model, to be 1 order of magnitude above its WHO-TEF value. By combining in vitro and in silico approaches, REPs were established for all WHO-TEF assigned compounds (except OCDD), which will provide future guidance in testing AhR-mediated responses of DLCs and to increase our understanding of species variation in AhR-mediated effects.
24.	Girgis, E., et al. (författare) Nanotoxicity of Gold and Gold-Cobalt Nanoalloy 2012 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 25:5, s. 1086-1098 Tidskriftsartikel (refereegranskat)abstract Nanotoxicology test of gold nanoparticles (Au NPs) and gold-cobalt (Au-Co) nanoalloy is an important step in their safety evaluation for biomedical applications. The Au and Au-Co NPs were prepared by reducing the metal ions using sodium borohydride (NaBH4) in the presence of polyvinyl pyrrolidone (PVP) as a capping material. The average size and shape of the nanoparticles (NPs) were characterized using high resolution transmission electron microscopy (HRTEM). Cobalt presence in the nanoalloy was confirmed by energy dispersive X-ray spectroscopy (EDX) analysis, and the magnetic properties of these particles were determined using a vibrating sample magnetometer (VSM). The Gold and gold-cobalt NPs of average size 15 +/- 1.5 nm were administered orally to mice with a dose of 80, 160, and 320 mg/kg per body weight (bw) using gavages. Samples were collected after 7 and 14 days of the treatment. The results indicated that the Au-Co NPs were able to induce significant alteration in the tumor-initiating genes associated with an increase of micronuclei (MNs) formation and generation of DNA adduct (8-hydroxy-2-deoxyguanosine, 8-OHdG) as well as a reduction in the glutathione peroxidase activity. This action of Au-Co NPs was observed using 160 and 320 mg/kg bw at both time intervals. However, Au NPs had much lower effects than Au-Co NPs on alteration in the tumor-initiating genes, frequency of MNs, and generation of 8-0HdG as well as glutathione peroxidase activity except with the highest dose of Au NPs. This study suggests that the potential to cause in vivo genetic and antioxidant enzyme alterations due to the treatment by Au-Co nanoalloy may be attributed to the increase in oxidative stress in mice.
25.	Goldstein, S., et al. (författare) Carbonate radical ion is the only observable intermediate in the reaction of peroxynitrite with CO2 2001 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 14:9, s. 1273-1276 Tidskriftsartikel (refereegranskat)abstract The reaction of ONOO- with CO2 at alkaline pH was recently reported to form a transient absorption with a maximum at 640 nm and a half-life of ca. 4 ms at 10 degreesC [Meli et al. (1999) Helv. Chim. Acta 82, 722-725]. This transient absorption was hardly affected by the presence of (NO)-N-., and therefore was attributed to the adduct ONOOC(O)O-. This conclusion contradicts all current experimental results as it suggests that the decomposition of this adduct via homolysis of the O-O bond into CO3.- and . NO2 is a minor pathway. In the present work the observations of Meli et al. will be shown to be artifacts resulting from light coming from the UV region. When these experiments are carried out in the presence of appropriate cutoff filters, the only observable intermediate formed in the reaction of ONOO- with CO2 at alkaline pH is the carbonate radical ion with a maximum at 600 nm. This transient absorption is not observed in the presence of (NO)-N-. or ferrocyanide. In the latter case ferricyanide is formed, and its yield was determined to be 66 +/-2% of the initial concentration of peroxynitrite. The reaction of ONOO- with 16 mM CO2 with and without ferrocyanide was also studied at pH 5.6-7.7 in the presence of 0.1 M phosphate, where both the initial pH and [CO2] remain constant. Under these conditions the rate constant of the decay of peroxynitrite was found to be identical to that of the formation of ferricyanide, indicating that ONOOC(O)(-) does not accumulate. These results confirm our earlier observations, i.e., the reaction of peroxynitrite with excess CO2 takes place via the formation of about 33% CO3.- and (NO2)-N-. radicals in the bulk of the solution.
26.	Goldstein, S., et al. (författare) Gibbs energy of formation of peroxynitrate-order restored 2001 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 14:6, s. 657-660 Tidskriftsartikel (refereegranskat)abstract In a recent publication [Nauser et al. (2001) Chem. Res. Toxicol. 14, 248-350], the authors estimated a value of 14 +/- 3 kcal/mol for the standard Gibbs energy of formation of ONOO- and argued that the experimental value of 16.6 kcal/mol [Merenyi, G., and Lind, J. (1998) Chem. Res. Toxicol. 11, 243-246] is in error. The lower value would suggest that the yield of free radicals during decomposition of ONOOH into nitrate is negligibly low, i.e., less than 0.5%, though within the large error limit given, the radical yield might vary between 0.003% and ca. 80%. The experimental value of 16.6 +/- 0.4 kcal/mol was based on the determination of the rate constant of the forward reaction in the equilibrium ONOO- reversible arrow (NO)-N-. and O-2(.-) by use of C(NO2)(4), an efficient scavenger of O-2(.-) which yields C(NO2)(3)(-). Nauser et al. reported that addition of.NO has no significant effect on the rate of formation of C(N02)3-, and therefore the formation of C(No-2)(3-) is due to a process other then reduction of C(NO2)(4) by O-2 (.-) In addition, they argued that Cu(II) nitrilotriacetate enhances the rate of peroxynitrite decomposition at pH 9.3 without reduction of Cu(II). In the present paper, we show that the formation of C(N02)3- due to the presence peroxynitrite is completely blocked upon addition of . NO, Furthermore, the acceleration of the rate of peroxynitrite decomposition at pH 9 in the presence of catalytic concentrations of SOD ([ONOO-]/[SOD] > 30) results in the same rate constant as that obtained in the presence of C(NO2)4. These results can only be rationalized by assuming that ONOO- homolyses into (NO)-N-. and O-2(.-) With k = 0.02 S-1 at 25 degreesC. Thus, the critical experiments suggested by Nauser et al. fully support the currently accepted thermodynamics as well as the mode of decomposition of the ONOOH/ONOO- system.
27.	Goldstein, S., et al. (författare) Reactions of nitric oxide, peroxynitrite, and carbonate radicals with nitroxides and their corresponding oxoammonium cations 2004 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 17:2, s. 250-257 Tidskriftsartikel (refereegranskat)abstract Cyclic nitroxides effectively protect biological systems against radical-induced damage. However, the mechanism of the reactions of nitroxides with nitrogen-derived reactive species and carbonate radicals is far from being elucidated. In the present study, the reactions of several representative piperidine- and pyrrolidine-based nitroxides with (NO)-N-., peroxynitrite, and CO3.- were investigated, and the results are as follows: (i) There is no evidence for any direct reaction between the nitroxides and the (NO)-N-.. In the presence of oxygen, the nitroxides are readily oxidized by (NO2)-N-., which is formed as an intermediate during autoxidation of (NO)-N-.. (ii) (NO)-N-. reacts with the oxoammonium cations to form nitrite and the corresponding nitroxides with k(1) = (9.8 +/- 0.2) x 10(3) and (3.7 +/- 0.1) x 10(5) M-1 s(-1) for the oxoammonium cations derived from 2,2,6,6-tetramethylpiperidine-1-oxyl (TPO) and 3-carbamoyl-proxyl (3-CP), respectively. (iii) CO3.- oxidizes all nitroxides tested to their oxoammonium cations with similar rate constants of (4.0 +/- 0.5) x 10(8) M-1 s(-1), which are about 3-4 times higher than those determined for H-abstraction from the corresponding hydroxylamines TPO-H and 4-OH-TPO-H. (iv) Peroxynitrite ion does not react directly with the nitroxides but rather with their oxoammonium cations with k(10) = (6.0 +/- 0.9) x 10(6) and (2.7 +/- 0.9) x 10(6) M-1 s(-1) for TPO+ and 3-CP+, respectively. These results provide a better insight into the complex mechanism of the reaction of peroxynitrite with nitroxides, which has been a controversial subject. The small effect of relatively low concentrations of nitroxides on the decomposition rate of peroxynitrite is attributed to their ability to scavenge efficiently (NO2)-N-. radicals, which are formed during the decomposition of peroxynitrite in the absence and in the presence Of CO2. The oxoammonium cations, thus formed, are readily reduced back to the nitroxides by ONOO-, while forming (NO)-N-. and O-2. Hence, nitroxides act as true catalysts in diverting peroxynitrite decomposition from forming nitrating species to producing nitrosating ones.
28.	Habermeyer, Michael, et al. (författare) Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity. 2005 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 18:9, s. 1395-404 Tidskriftsartikel (refereegranskat)abstract In the present study, we investigated the effect of anthocyanidins on human topoisomerases I and II and its relevance for DNA integrity within human cells. Anthocyanidins bearing vicinal hydroxy groups at the B-ring (delphinidin, DEL; cyanidin, CY) were found to potently inhibit the catalytic activity of human topoisomerases I and II, without discriminating between the IIalpha and the IIbeta isoforms. However, in contrast to topoisomerase poisons, DEL and CY did not stabilize the covalent DNA-topoisomerase intermediates (cleavable complex) of topoisomerase I or II. Using recombinant topoisomerase I, the presence of CY or DEL (> or = 1 microM) effectively prohibited the stabilization of the cleavable complex by the topoisomerase I poison camptothecin. We furthermore investigated whether the potential protective effect vs topoisomerase I poisons is reflected also on the cellular level, affecting the DNA damaging properties of camptothecin. Indeed, in HT29 cells, low micromolar concentrations of DEL (1-10 microM) significantly diminished the DNA strand breaking effect of camptothecin (100 microM). However, at concentrations > or = 50 microM, all anthocyanidins tested (delphinidin, cyanidin, malvidin, pelargonidin, and paeonidin), including those not interfering with topoisomerases, were found to induce DNA strand breaks in the comet assay. All of these analogues were able to compete with ethidium bromide for the intercalation into calf thymus DNA and to replace the minor groove binder Hoechst 33258. These data indicate substantial affinity to double-stranded DNA, which might contribute at least to the DNA strand breaking effect of anthocyanidins at higher concentrations (> or = 50 microM).
29.	Hagvall, Lina, 1978, et al. (författare) Experimental and Theoretical Investigations of the Autoxidation of Geranial: A Dioxolane Hydroperoxide Identified as a Skin Sensitizer. 2011 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. Tidskriftsartikel (refereegranskat)abstract The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.
30.	Hagvall, Lina, 1978, et al. (författare) Fragrance compound geraniol forms contact allergens on air exposure. Identification and quantification of oxidation products and effect on skin sensitization 2007 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 20:5, s. 807-814 Tidskriftsartikel (refereegranskat)abstract Fragrances are common causes of contact allergy. Geraniol (trans-3,7-dimethyl-2,6-octadiene-1-ol) is an important fragrance terpene. It is considered a weak contact allergen and is used for fragrance allergy screening among consecutive dermatitis patients. Analogous to other monoterpenes studied, such as limonene and linalool, geraniol has the potential to autoxidize on air exposure and form highly allergenic compounds. The aim of the present study was to investigate and propose a mechanism for the autoxidation of geraniol at room temperature. To investigate whether allergenic compounds are formed, the sensitizing potency of geraniol itself, air-exposed geraniol, and its oxidation products was determined using the local lymph node assay in mice. The results obtained show that the allylic alcohol geraniol follows an oxidation pattern different from those of linalool and limonene, which autoxidize forming hydroperoxides as the only primary oxidation products. The autoxidation of geraniol follows two paths, originating from allylic hydrogen abstraction near the two double bonds. From geraniol, hydrogen peroxide is primarily formed together with aldehydes geranial and neral from a hydroxyhydroperoxide. In addition, small amounts of a hydroperoxide are formed, analogous to the formation of the major linalool hydroperoxide. The autoxidation of geraniol greatly influenced the sensitizing effect of geraniol. The oxidized samples had moderate sensitizing capacity, quite different from that of pure geraniol. The hydroperoxide formed is believed to be the major contributor to allergenic activity, together with the aldehydes geranial and neral. On the basis of the present study and previous experience, we recommend that the possibility of autoxidation and the subsequent formation of contact allergenic oxidation products are considered in risk assessments performed on fragrance terpenes.
31.	Hofer, T, et al. (författare) Optimization of the workup procedure for the analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine with electrochemical detection 2002 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 15:3, s. 426-432 Tidskriftsartikel (refereegranskat)
32.	Hofer, T, et al. (författare) Reduction of oxidation during the preparation of DNA and analysis of 8-hydroxy-2'-deoxyguanosine 1998 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 11:8, s. 882-887 Tidskriftsartikel (refereegranskat)
33.	Holmdahl, Meirav, et al. (författare) Structure-Immune Response Relationships of Hapten-Modified Collagen II Peptides in a T-Cell Model of Allergic Contact Dermatitis. 2008 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 21, s. 1514-1523 Tidskriftsartikel (refereegranskat)abstract Allergic contact dermatitis (ACD) is mediated by T cells that specifically recognize hapten-modified peptides. T cells are known to recognize antigens as short processed peptides bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). It has previously been demonstrated that T cells can specifically recognize carbohydrates on the lysine at position 264 of the immunodominant (256-273) sequence from type II collagen (CII) and that such recognition is critical for the development of arthritis in mice and may play a role in rheumatoid arthritis in humans. In the present study, we have used this approach in modeling ACD, but instead of the carbohydrate, the strong sensitizer 2,4-dinitrofluorobenzene (DNFB) is bound to the epsilon-amine of the lysine at position 264. Specific T-cell hybridomas of this antigenic peptide, with dinitrophenyl (Dnp) on the epsilon-amine of lysine at position 264 (CIILysDnp 3), were established from mice immunized with CIILysDnp 3. In an immune response assay, these T-cell hybridomas were tested with a series of new synthetic hapten-modified peptides, all chemically identical except for the stereochemimistry ( d, l) and the length of the position-264 amino acid side chain bonding the hapten. The T-cell hybridomas recognized the CIILysDnp 3 peptide used for immunization; interestingly, they also recognized the CII peptide with a one-carbon-longer side chain (homolysine), CIIhLysDnp 6, and CIIAlaPipDnp 11, having a ring structure analogous to that of lysine with the same number of carbons in the bonding chain as in the CIILysDnp 3 peptide used for immunization. Dnp-modified CII peptides with a shorter bonding chain produced no immune response. These data demonstrate that the T-cell recognition of the Dnp-modified peptides is highly specific and moreover dependent on the length of the amino acid side chain that bonds the Dnp.
34.	Huerta-García, Elizabeth, et al. (författare) Internalization of Titanium Dioxide Nanoparticles Is Mediated by Actin-Dependent Reorganization and Clathrin- and Dynamin-Mediated Endocytosis in H9c2 Rat Cardiomyoblasts 2019 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 32:4, s. 578-588 Tidskriftsartikel (refereegranskat)abstract Titanium dioxide nanoparticles (TiO2 NPs) are widely used for industrial and commercial applications. Once inside the body, they translocate into the bloodstream and reach different areas of the cardiovascular system including the heart, increasing the risk of developing cardiovascular diseases; consequently, the investigation of their interaction with cardiac cells is required. We previously showed that TiO2 NPs are internalized by H9c2 rat cardiomyoblasts, and here, we examined the molecular mechanisms underlying this process. TiO2 NPs internalization was evaluated by transmission electron microscopy, time-lapse microscopy, and flow cytometry. Changes in the actin cytoskeleton were studied by phalloidin staining. Endocytic uptake mechanisms for nanoparticles were probed with chemical inhibitors, whereas clathrin and dynamin expression was measured by Western blot. Cellular uptake of TiO2 NPs occurred early after 30 min exposure, and large aggregates were observed after 1 h. Actin cytoskeleton reorganization included cell elongation plus lower density and stability of actin fibers. Cytochalasin-D inhibited TiO2 NPs uptake, indicating actin-mediated internalization. Dynamin and clathrin levels increased early after TiO2 NPs exposure, and their inhibition reduced nanoparticle uptake. Therefore, TiO2 NPs internalization by H9c2 rat cardiomyoblasts involves actin cytoskeleton reorganization and clathrin/dynamin-mediated endocytosis.
35.	Jain, Sankalp, et al. (författare) Combining In Vivo Data with In Silico Predictions for Modeling Hepatic Steatosis by Using Stratified Bagging and Conformal Prediction 2021 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 34:2, s. 656-668 Tidskriftsartikel (refereegranskat)abstract Hepatic steatosis (fatty liver) is a severe liver disease induced by the excessive accumulation of fatty acids in hepatocytes. In this study, we developed reliable in silico models for predicting hepatic steatosis on the basis of an in vivo data set of 1041 compounds measured in rodent studies with repeated oral exposure. The imbalanced nature of the data set (1:8, with the "steatotic" compounds belonging to the minority class) required the use of meta-classifiers-bagging with stratified under-sampling and Mondrian conformal prediction-on top of the base classifier random forest. One major goal was the investigation of the influence of different descriptor combinations on model performance (tested by predicting an external validation set): physicochemical descriptors (RDKit), ToxPrint features, as well as predictions from in silico nuclear receptor and transporter models. All models based upon descriptor combinations including physicochemical features led to reasonable balanced accuracies (BAs between 0.65 and 0.69 for the respective models). Combining physicochemical features with transporter predictions and further with ToxPrint features gave the best performing model (BAs up to 0.7 and efficiencies of 0.82). Whereas both meta-classifiers proved useful for this highly imbalanced toxicity data set, the conformal prediction framework also guarantees the error level and thus might be favored for future studies in the field of predictive toxicology.
36.	Jeppsson, Marina, et al. (författare) Identification of Covalent Binding Sites of Phthalic Anhydride in Human Hemoglobin. 2008 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; Oct 3, s. 2156-2163 Tidskriftsartikel (refereegranskat)abstract Phthalic anhydride (PA) is a reactive low molecular weight compound used in the chemical industry. The exposure of PA may lead to work-related airway diseases such as rhinitis, chronic bronchitis, and asthma. The exposure gives rise to an increase in hapten-specific IgG antibodies in workers but with a low presence of specific IgE antibodies. In this study, the binding of PA to human hemoglobin (Hb) in vitro was investigated. Trypsin and Pronase E digestion, LC, LC/MS/MS, GC/MS analysis, and nanoelectrospray hybrid quadrupole time-of-flight MS were used to identify the adducted amino acids of the synthesized PA-Hb conjugates. In the conjugate with the molar ratio 1:0.1, a total of six adducted amino acids were identified. N-Terminal valine was found adducted in both the alpha- and the beta-chains as well as a total of four lysines, Val 1, Lys 16, and Lys 61 on the alpha-chain and Val 1, Lys 66, and Lys 144 on the beta-chain. Two types of lysine adducts were found, a phthalamide and a phthalimide. It was also found that PA differs in its binding site as compared to hexahydrophthalic anhydride. The result of this study suggests several interesting applications of biological monitoring.
37.	Johansson, Staffan, 1976, et al. (författare) Carbon- and Oxygen-Centered Radicals Are Equally Important Haptens of Allylic Hydroperoxides in Allergic Contact Dermatitis 2008 Ingår i: Chem. Res. Toxicol.. - : American Chemical Society (ACS). ; 21:8, s. 1536-1547 Tidskriftsartikel (refereegranskat)abstract Limonene is one of the most commonly used fragrance compounds in western countries today. When exposed to air, it autoxidises, forming hydroperoxides that are strong contact allergens. To cause allergic contact dermatitis (ACD), the hydroperoxides are considered to bind covalently to proteins in the skin via a radical pathway. Consequently, the nature and reactions of the radicals formed from the hydroperoxides are important. We have examined the radical formation from, and sensitizing potential of, three allylic hydroperoxides. Two of these are found in the oxidation mixture of limonene, while the third is a synthetic structural analogue. The identity of the radicals formed from these hydroperoxides has been studied in radical trapping experiments. Chemical trapping experiments were performed using 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride [Fe(III)TPPCl3] as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. Electron paramagnetic resonance experiments using photolysis for initiation were performed with and without 5-diethoxy-phosphoryl-5-methyl-1-pyrroline N-oxide. Our results demonstrate the ability of the studied hydroperoxides to form peroxyl, allyloxyl, and oxiranylcarbinyl radicals. These radicals can potentially react with proteins to form immunogenic hapten−protein complexes relevant for ACD. The sensitizing potency of the hydroperoxides was studied in the murine local lymph node assay. All three hydroperoxides were found to be potent sensitizers with some variations, which can be related to the identity and quantity of the radicals formed. The results indicate that both carbon- and oxygen-centered radicals are important intermediates in the formation of hapten−protein complexes and that the sensitizing potency of the hydroperoxides is related to their structures.
38.	Johansson, Staffan G H, et al. (författare) Structural Influence on Radical Formation and Sensitizing Capacity of Alkylic Limonene Hydroperoxide Analogues in Allergic Contact Dermatitis. 2010 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 23:3, s. 677-688 Tidskriftsartikel (refereegranskat)abstract Hydroperoxides are known to be strong contact allergens and a common cause of contact allergy. They are easily formed by the autoxidation of, for example, fragrance terpenes, compounds that are common in perfumes, cosmetics, and household products. A requirement of the immunological mechanisms of contact allergy is the formation of an immunogenic hapten-protein complex. For hydroperoxides, a radical mechanism is postulated for this formation. In our previous investigations of allylic limonene hydroperoxides, we found that the formation of carbon- and oxygen-centered radicals, as well as the sensitizing capacity, is influenced by the structure of the hydroperoxides. The aim of the present work was to further investigate the connection between structure, radical formation, and sensitizing capacity by studying alkylic analogues of the previously investigated allylic limonene hydroperoxides. The radical formation was studied in radical-trapping experiments employing 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. We found that the investigated hydroperoxides initially form carbon- and oxygen-centered radicals that subsequently form alcohols and ketones. Trapped carbon-centered radicals and nonradical products were isolated and identified. Small changes in structure, like the omission of the endocyclic double bond or the addition of a methyl group, resulted in large differences in radical formation. The results indicate that alkoxyl radicals seem to be more important than carbon-centered radicals in the immunogenic complex formation. The sensitizing capacities were studied in the murine local lymph node assay (LLNA), and all hydroperoxides tested were found to be potent sensitizers. For two of the hydroperoxides investigated, the recently suggested thiol-ene reaction is a possible mechanism for the formation of immunogenic complexes. For the third investigated, fully saturated, hydroperoxide, the thiol-ene mechanism is not possible for immunogenic complex formation. This strongly indicates that several radical reaction pathways for immunogenic complex formation of limonene hydroperoxides are active in parallel.
39.	Johansson, Staffan, 1976, et al. (författare) Mechanistic Proposal for the Formation of Specific Immunogenic Complexes via a Radical Pathway: A Key Step in Allergic Contact Dermatitis to Olefinic Hydroperoxides 2009 Ingår i: Chem. Res. Toxicol.. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1774-1781 Tidskriftsartikel (refereegranskat)abstract The widespread use of scented products causes an increase of allergic contact dermatitis to fragrance compounds in Western countries today. Many fragrance compounds are prone to autoxidation, forming hydroperoxides as their primary oxidation products. Hydroperoxides are known to be strong allergens and to form specific immunogenic complexes. However, the mechanisms for the formation of the immunogenic complexes are largely unknown. We have investigated this mechanism for (5R)-5-isopropenyl-2-methyl-2-cyclohexene-1-hydroperoxide (Lim-2-OOH) by studying the formation of adducts in the reaction between this hydroperoxide and 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (Fe(III)TPPCl) in the presence of protected cysteine (NAc-Cys-OMe) or glutathione (GSH). Isolated adducts originate from the addition of the thiol group of NAc-Cys-OMe over the carbon−carbon double bonds of carvone. Furthermore, adducts between NAc-Cys-OMe and carveol as well as between GSH and carvone have been identified. The formation of these adducts most likely proceeds via the radical thiol−ene mechanism. The addition of a terpene moiety to cysteine offers an explanation of the specificity of the immune response to structurally different hydroperoxides. These results also explain the lack of cross-reactivity between carvone and Lim-2-OOH. In conclusion, we propose that immunogenic complexes of olefinic hydroperoxides can be formed via the radical thiol−ene mechanism. These complexes will be specific for the individual olefinic hydroperoxides due to the inclusion of a terpene moiety derived from the hydroperoxide.
40.	Karlberg, Ann-Therese, 1947, et al. (författare) Allergic Contact Dermatitis––Formation, Structural Requirements, and Reactivity of Skin Sensitizers 2008 Ingår i: Chem. Res. Toxicol.. - : American Chemical Society (ACS). ; 21:1, s. 53-69 Tidskriftsartikel (refereegranskat)abstract Contact allergy is caused by a wide range of chemicals after skin contact. Its clinical manifestation, allergic contact dermatitis (ACD), is developed upon repeated contact with the allergen. This perspective focuses on two areas that have yielded new useful information during the last 20 years: (i) structure–activity relationship (SAR) studies of contact allergy based on the concept of hapten-protein binding and (ii) mechanistic investigations regarding activation of nonsensitizing compounds to contact allergens by air oxidation or skin metabolism. The second area is more thoroughly reviewed since the full picture has previously not been published. Prediction of the sensitizing capacity of a chemical is important to avoid outbreaks of ACD in the population. Much research has been devoted to the development of in vitro and in silico predictive testing methods. Today, no method exists that is sensitive enough to detect weak allergens and that is robust enough to be used for routine screening. To cause sensitization, a chemical must bind to macromolecules (proteins) in the skin. Expert systems containing information about the relationship between the chemical structure and the ability of chemicals to haptenate proteins are available. However, few designed SAR studies based on mechanistic investigations of prohaptens have been published. Many compounds are not allergenic themselves but are activated in the skin (e.g., metabolically) or before skin contact (e.g., via air oxidation) to form skin sensitizers. Thus, more basic research is needed on the chemical reactions involved in the antigen formation and the immunological mechanisms. The clinical importance of air oxidation to activate nonallergenic compounds has been demonstrated. Oxidized fragrance terpenes, in contrast to the pure terpenes, gave positive patch test reactions in consecutive dermatitis patients as frequently as the most common standard allergens. This shows the importance of using compounds to which people are exposed when screening for ACD in dermatology clinics.
41.	Karlberg, Ann-Therese, 1947, et al. (författare) Letter to the Editor Regarding the Article by Natsch et al., 2015. 2015 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 28:11, s. 2079-81 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
42.	Karlsson, HL, et al. (författare) Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes 2008 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 21:9, s. 1726-1732 Tidskriftsartikel (refereegranskat)
43.	Karlsson, HL, et al. (författare) Mechanisms related to the genotoxicity of particles in the subway and from other sources 2008 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 21:3, s. 726-731 Tidskriftsartikel (refereegranskat)
44.	Karlsson, HL, et al. (författare) Subway particles are more genotoxic than street particles and induce oxidative stress in cultured human lung cells 2005 Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 18:1, s. 19-23 Tidskriftsartikel (refereegranskat)
45.	Karlsson, Helen, et al. (författare) Wear Particles from Studded Tires and Granite Pavement Induce Pro-inflammatory Alterations in Human Monocyte-Derived Macrophages : A Proteomic Study. 2011 Ingår i: Chemical Research in Toxicology. - : American Chemical Society. - 0893-228X .- 1520-5010. ; 24, s. 45-53 Tidskriftsartikel (refereegranskat)abstract Airborne particulate matter is considered to be one of the environmental contributors to the mortality in cancer, respiratory, and cardiovascular diseases. For future preventive actions, it is of major concern to investigate the toxicity of defined groups of airborne particles and to clarify their pathways in biological tissues. To expand the knowledge beyond general inflammatory markers, this study examined the toxicoproteomic effects on human monocyte derived macrophages after exposure to wear particles generated from the interface of studded tires and a granite-containing pavement. As comparison, the effect of endotoxin was also investigated. The macrophage proteome was separated using two-dimensional gel electrophoresis. Detected proteins were quantified, and selected proteins were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Among analyzed proteins, seven were significantly decreased and three were increased by exposure to wear particles as compared to unexposed control cells. Endotoxin exposure resulted in significant changes in the expression of six proteins: four decreased and two increased. For example, macrophage capping protein was significantly increased after wear particle exposure only, whereas calgizzarin and galectin-3 were increased by both wear particle and endotoxin exposure. Overall, proteins associated with inflammatory response were increased and proteins involved in cellular functions such as redox balance, anti-inflammatory response, and glycolysis were decreased. Investigating the effects of characterized wear particles on human macrophages with a toxicoproteomic approach has shown to be useful in the search for more detailed information about specific pathways and possible biological markers.
46.	Karlsson, Isabella, 1980, et al. (författare) Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen 2014 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:7, s. 1294-1303 Tidskriftsartikel (refereegranskat)abstract Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-L-Trp ethyl ester and L-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
47.	Karlsson, Isabella, et al. (författare) Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity-Isosorbide-Based Bis-Epoxides 2023 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 36:2, s. 281-290 Tidskriftsartikel (refereegranskat)abstract Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bisepoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.
48.	Karlsson, Isabella, 1980, et al. (författare) Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens 2009 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1881-1892 Tidskriftsartikel (refereegranskat)abstract One of the most frequently observed photoallergens today is the sunscreen agent 4-tert-butyl-4′-methoxy dibenzoylmethane (1a). The structurally similar compound, 4-isopropyldibenzoylmethane (1b), was a common cause of sunscreen allergy in the eighties and early nineties but was removed from the market in 1993 and replaced with dibenzoylmethane 1a. We have studied the photodegradation of the dibenzoylmethane 1a, to better understand how these substances cause an immune reaction. Several expected degradation products were formed and identified. Of these, arylglyoxals and benzils were of particular interest because they were unexplored as potential contact allergens. The allergenic potential of photodegraded 1a was evaluated by screening the formed arylglyoxals and benzils for their sensitizing capacity in the murine local lymph node assay. The arylglyoxals were found to be strong sensitizers. They were also found to be highly reactive toward the nucleophile arginine, which indicates that the immunogenic hapten-protein complex could be formed via an electrophilic-nucleophilic pathway. By varying the electron-withdrawing or -donating capacity of the substituent in the para position of the arylglyoxal, the electronic effects were shown to have no significant impact on either the sensitizing or the electrophilic power of arylglyoxals. Thus, a change in the substitution pattern of the parent dibenzoylmethane will not influence the sensitizing capacity of the products formed from them upon photodegradation. Furthermore, the combined studies of benzils, using the local lymph node assay and a cell proliferation assay, indicate that the benzils are cytotoxic rather than allergenic. Taken together, this study presents strong indication that photocontact allergy to dibenzoylmethanes is caused by the arylglyoxals that are formed upon photodegradation.
49.	Kessler, Amanda, et al. (författare) Adsorption of Horseradish Peroxidase on Metallic Nanoparticles : Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate 2021 Ingår i: Chemical Research in Toxicology. - : American Chemical Society. - 0893-228X .- 1520-5010. ; 350, s. S215-S216 Tidskriftsartikel (refereegranskat)abstract The fluorescent probe 2′,7′-dichlorofluorescein diacetate (DCFH-DA) together with the enzyme horseradish peroxidase (HRP) is widely used in nanotoxicology to study acellular reactive oxygen species (ROS) production from nanoparticles (NPs). This study examined whether HRP adsorbs onto NPs of Mn, Ni, and Cu and if this surface process influences the extent of metal release and hence the ROS production measurements using the DCFH assay in phosphate buffered saline (PBS), saline, or Dulbecco's modified Eagle's medium (DMEM). Adsorption of HRP was evident onto all NPs and conditions, except for Mn NPs in PBS. The presence of HRP resulted in an increased release of copper from the Cu NPs in PBS and reduced levels of nickel from the Ni NPs in saline. Both metal ions in solution and the adsorption of HRP onto the NPs can change the activity of HRP and thus influence the ROS results. The effect of HRP on the NP reactivity was shown to be solution chemistry dependent. Most notable was the evident affinity/adsorption of phosphate toward the metal NPs, followed by a reduced adsorption of HRP, the concomitant reduction in released manganese from the Mn NPs, and increased levels of released metals from the Cu NPs in PBS. Minor effects were observed for the Ni NPs. The solution pH should be monitored since the release of metals can change the solution pH and the activity of HRP is known to be pH-dependent. It is furthermore essential that solution pH adjustments are made following the addition of NaOH during diacetyl removal of DCFH-DA. Even though not observed for the given exposure conditions of this study, released metal ions could possibly induce agglomeration or partial denaturation of HRP, which in turn could result in steric hindrance for H2O2 to reach the active site of HRP. This study further emphasizes the influence of HRP on the background kinetics, its solution dependence, and effects on measured ROS signals. Different ways of correcting for the background are highlighted, as this can result in different interpretations of generated results. The results show that adsorption of HRP onto the metal NPs influenced the extent of metal release and may, depending on the investigated system, result in either under- or overestimated ROS signals if used together with the DCFH assay. HRP should hence be used with caution when measuring ROS in the presence of reactive metallic NPs. © 2021 The Authors.
50.	Kessler, Amanda, et al. (författare) Unravelling the Mechanistic Understanding of Metal Nanoparticle-Induced Reactive Oxygen Species Formation : Insights from a Cu Nanoparticle Study 2023 Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 36:12, s. 1891-1900 Tidskriftsartikel (refereegranskat)abstract Humans can be exposed to engineered and nonintentionally formed metal and metal oxide nanoparticles (Me NPs) in occupational settings, in public transportation areas, or by means of contact with different consumer products. A critical factor in the toxic potency of Me NPs is their ability to induce oxidative stress. It is thus essential to assess the potential reactive oxygen species (ROS) formation properties of Me NPs. A common way to assess the relative extent of ROS formation in vitro is to use fluorescence spectroscopy with the DCFH-DA (2 ',7'-dichlorofluorescein diacetate) probe, with and without HRP (horseradish peroxidase). However, this method does not provide any information about specific ROS species or reaction mechanisms. This study investigated the possibility of using complementary techniques to obtain more specific information about formed ROS species, both the type and reaction mechanisms. Cu NPs in PBS (phosphate buffered saline) were chosen as a test system to have the simplest (least interference from other components) aqueous solution with a physiologically relevant pH. ROS formation was assessed using fluorescence by means of the DCFH-DA method (information on relative amounts of oxygen radicals without selectivity), the Ghormley's triiodide method using UV-vis spectrophotometry (concentrations of H2O2), and electron paramagnetic resonance with DMPO as the spin-trap agent (information on specific oxygen radicals). This approach elucidates that Cu NPs undergo ROS-generating corrosion reactions, which previously have not been assessed in situ. In the presence of H2O2, and based on the type of oxygen radical formed, it was concluded that released copper participates in Haber-Weiss and/or Fenton reactions rather than in Fenton-like reactions. The new combination of techniques used to determine ROS induced by Me NPs provides a way forward to gain a mechanistic understanding of Me NP-induced ROS formation, which is important for gaining crucial insight into their ability to induce oxidative stress.

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