| 1. |
- Bergander, Linda, 1972-
(author)
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Formation and metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole - a light-induced Ah-receptor ligand
- 2005
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Doctoral thesis (other academic/artistic)abstract
- The aryl hydrocarbon receptor (AhR) is a ligand dependent transcription factor ubiquitously expressed in mammalian cells. It is a genetically ancient protein mostly known for binding the extremely toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Binding to the AhR explains the variety of toxic responses of TCDD as well as the induction of several drug metabolizing enzymes. Induction of cytochrome P4501A1 (CYP1A1) is the most well characterized of the AhR regulated responses. The physiological functions of AhR and the endogenous ligand(s) for the receptor are under investigation but are not yet unraveled. Several tryptophan (TRP) derived indol-containing compounds have been reported to possess AhR affinity/CYP1A1 inducing capacity and TRP mediates CYP1A1 induction by UV light. The TRP photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ) has the highest AhR affinity described so far and it causes a rapid and transient induction of the CYP1A1 gene in human cells. A number of reports on constitutive CYP1A1 activity in cultured cells is therefore most likely explained by the presence of TRP-derived AhR ligands in cell culture media. The aims of the studies were to investigate the impact of FICZ and FICZ metabolism on CYP1A1 gene regulation, to explore the metabolic fate of FICZ and to identify whether normal laboratory light could lead to formation of FICZ and thereby contribute to earlier observed CYP1A1 inducing effects by cell culture media. Metabolic studies using fractions of Aroclor-induced and non-induced rat liver and human liver as well as heterologously expressed enzymes revealed that FICZ can be efficiently metabolized by the CYP enzymes 1A1 and 1A2 and by an unknown cytosolic enzyme, to a number of hydroxylated and other oxidized metabolites. All of the hitherto identified 11 hydroxylated metabolites of FICZ are prone to conjugation reactions by glucuronosyltranferases and sulfotransferases. The metabolites formed by human enzymes are primarily sulfated. Thus, the sulfated metabolites of FICZ will be crucial in the future analyzes of FICZ formation in vivo. FICZ was identified to be formed, not only by UV illumination, but also by normal laboratory light. The constitutive CYP1A1 activity was significantly induced through the formation of several TRP related photoproducts in light-exposed medium. One of these photoproducts was identified as FICZ. Thus, the TRP photoproduct, FICZ, fits into a model in which FICZ auto-regulates the expression of induced enzymes. It is hypothesized that FICZ might function as a chemical messenger that activates AhR in response to light and might be one of several possible endogenous AhR ligands.
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| 2. |
- Bergander, Linda, et al.
(author)
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Metabolic fate of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole
- 2004
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In: Chemico-Biological Interactions. - : Elsevier BV. - 0009-2797. ; 149:2-3, s. 151-164
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Journal article (peer-reviewed)abstract
- The physiological role of the aryl hydrocarbon receptor (AhR), a member of the basic helix-loop-helix PER-ARNT-SIM (PAS) transcription factor family is not known. We have suggested that the AhR is involved in light signaling through binding of photoproducts with high AhR affinity. This suggestion is based on (i) the high AhR affinity of the tryptophan photoproduct formylindolo[3,2-b]carbazole (FICZ), (ii) the induction of rapid and transient expression of AhR-regulated genes by FICZ and by extracts of UV-irradiated tryptophan as well as (iii) the fact that light induces the AhR-regulated cytochrome P450s CYP1A1, CYP1B1 and CYP2S1. The transient mRNA expression caused by light and tryptophan photoproducts suggests that the biotransformation enzymes induced by AhR activation take part in a metabolic degradation of the natural AhR ligand. This study aimed at identifying the involvement of phase I and phase II enzymes in the metabolic degradation of FICZ. A cytochrome P450-dependent metabolism of FICZ giving rise to preferentially mono- and di-hydroxylated derivatives has earlier been reported. In the present study, rat and human hepatic S9 mixes were employed together with specific enzyme inhibitors and cofactors. Compared to the Aroclor-induced rat liver S9, the non-induced rat liver S9 and the human liver S9 caused a more complex metabolite profile of FICZ. The CYP1A1 enzyme was confirmed to be the most important enzyme for the first step in the metabolism. CYP1A2 was found to have overlapping specificity with CYP1A1 being able to form the same major metabolites although with different kinetics. CYP1B1 turned out to be preferentially involved in the further metabolism of dihydroxylated metabolites. Microsomal epoxide hydrolase, and as yet not identified forms of sulphotransferases and glucuronosyltransferases were also found to take part in the metabolic degradation of FICZ. Thus, tryptophan photoproducts fit into a model in which the ligand-activated AhR signaling is autoregulated by the induced metabolic enzymes.
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| 3. |
- Mohammadi-Bardbori, Afshin, et al.
(author)
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NADPH Oxidase-Dependent Mechanism Explains How Arsenic and Other Oxidants Can Activate Aryl Hydrocarbon Receptor Signaling
- 2015
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 28:12, s. 2278-2286
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Journal article (peer-reviewed)abstract
- The mechanisms explaining arsenic toxicity are not well understood, but physiological consequences of stimulated aryl hydrocarbon receptor (AHR) signaling both directly and through cross-talk with other pathways have been indicated. The aim of this study was to establish how arsenic interacts with AHR-mediated transcription. The human hepatoma cell line (HepG2-XRE-Luc) carrying a luciferase reporter under the control of two AHR response elements (AHREs) and immortalized human keratinocytes (HaCaT) were exposed to sodium arsenite (NaAsO2; As3+), alone or in combination with the endogenous high affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Luciferase activity, cytochrome P4501A1 (CYP1A1) activity, oxidative stress-related responses, metabolic clearance of FICZ, and NADPH:oxidase (NOX) activity as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent gene expression were measured. Arsenic inhibited,CYP1A1 enzyme activity and reduced the metabolic clearance of FICZ. Arsenic also led to activated CYP1A1 transcription but only in cells grown in medium containing trace amounts of the endogenous ligand FICZ, pointing to an indirect mechanism of activation. Initially, arsenic caused dose-dependent inhibition of FICZ-activated AHR signaling, disturbed intracellular GSH status, and increased expression of oxidative stress-related genes. Silencing of NOX4, addition of N-acetylcystein, or pretreatment with arsenic itself attenuated the initial dose-dependent inhibition of AHR signaling. Arsenic pretreatment led to elevated GSH levels and sensitized the cells to ligaild-dependent AHR signaling, while silencing of Nrf2 significantly reduced arsenic-mediated, activation of the AHR. In addition, influence of NOX on AHR activation was also observed in cells treated with the SH-reactive metals cadmium, mercury, and nickel. Together, the results suggest that SH-reactive agents via a new and possibly general NOX/H2O2-dependent mechanism can interfere with the endogenous regulation of the AHR.
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| 4. |
- Mohammadi-Bardbori, Afshin, et al.
(author)
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Quercetin, Resveratrol, and Curcumin Are Indirect Activators of the Aryl Hydrocarbon Receptor (AHR)
- 2012
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 25:9, s. 1878-1884
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Journal article (peer-reviewed)abstract
- Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.
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| 5. |
- Oberg, Mattias, et al.
(author)
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Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity.
- 2005
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In: Toxicol Sci. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 85:2, s. 935-43
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Journal article (peer-reviewed)abstract
- The presence of high affinity ligands for the aryl hydrocarbon receptor (AhR) in cell culture medium has generally been overlooked. Such compounds may confound mechanistic studies of the important AhR regulatory network. Numerous reports have described that light exposed cell culture medium induces AhR-dependent activity. In this study, we aimed at identifying the causative substance(s). A three-dimensional factorial design was used to study how the background activity of CYP1A1 in a rat hepatoma cell line (MH1C1) was controlled by photoproducts formed in the medium exposed to normal laboratory light. The light induced activity was found to be tryptophan dependent, but independent of riboflavin and other components in the medium. The light exposed medium showed the same transient enzyme inducing activity in vitro as the AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). This substance, which we have previously identified as being formed in UV-exposed tryptophan solutions, is a substrate for CYP1A1 and it has a higher AhR binding affinity than TCDD. Several tryptophan related photoproducts were detected in the light-exposed medium. For the first time one of the formed photoproducts was identified as FICZ with bioassay driven fractionation coupled with HPLC/MS. These results clearly show that tryptophan derived AhR ligands, which have been suggested to be endogenous AhR ligands, influence the background levels of CYP1A1 activity in cells in culture.
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| 6. |
- Rannug, Agneta, et al.
(author)
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The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation
- 2018
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In: Critical reviews in toxicology. - : Informa UK Limited. - 1040-8444 .- 1547-6898. ; 48:7, s. 555-574
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Research review (peer-reviewed)abstract
- The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.
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| 7. |
- Smirnova, Anna, et al.
(author)
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Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ
- 2016
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 29:1, s. 75-86
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Journal article (peer-reviewed)abstract
- Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.
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| 8. |
- Wincent, Emma, 1978-
(author)
-
Direct and indirect mechanisms for aryl hydrocarbon receptor activation mediated by 6-formylindolo[3,2-b]carbazole
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- The aryl hydrocarbon receptor (AhR) is mostly recognized for mediating the adverse effects of dioxins. In addition, endogenous activation of the AhR seems to have important biological functions. Several studies have demonstrated an activation of the receptor when no exogenous ligand was added. Furthermore, different physical stimuli such as UV irradiation, fluid shear stress, and hyperoxia have been shown to induce AhR-dependent transcriptional activity. Together these reports indicate either the presence of endogenous ligands or a non-ligand dependent activation. While the mechanisms behind such responses are still elusive, formation of tryptophan photoproducts with high AhR-affinity has been suggested to explain the activation observed after UVB irradiation. The photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) has been proposed to be an endogenous signal substance, and is the focus of the present thesis. The objective of the work presented in this thesis was to further characterize the formation and metabolism of FICZ, to identify the biotransforming enzymes required for its metabolism, and subsequently to isolate FICZ-derived metabolites in human urine. The studies reveal that FICZ is an excellent substrate for CYP1 enzymes resulting in an efficient metabolism and rapid clearance of FICZ, and a reduced or abolished affinity for the AhR. The hydroxylated metabolites are in turn very good substrates for sulfo-conjugation, and monosulfated derivatives of FICZ were identified in human urine, proving the existence of FICZ in vivo. Furthermore, disturbing the CYP1-dependent metabolic clearance of FICZ efficiently attenuated the rapid depletion of intracellular levels of FICZ, and resulted in a delayed and prolonged AhR-activation. These results suggest that inhibition of degradation of FICZ provides a potent mechanism for indirect regulation of the AhR response. The high affinity and AhR activating capacity, together with its rapid clearance by AhR regulated biotransforming enzymes and presence in humans in vivo, all strengthen the hypothesis that FICZ is an endogenous ligand for the AhR and an important biological signaling molecule.
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| 9. |
- Wincent, Emma, et al.
(author)
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Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor
- 2012
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:12, s. 4479-4484
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Journal article (peer-reviewed)abstract
- Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3'-methoxy-4'-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.
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| 10. |
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| 11. |
- Wincent, Emma, et al.
(author)
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The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans
- 2009
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:5, s. 2690-2696
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Journal article (peer-reviewed)abstract
- Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine-disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived from Trp, in particular 6-formylindolo[3,2-b]carbazole (FICZ), acts as natural high affinity ligands for this receptor. Here we describe seven new FICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolites and two sulfoconjugates, and we demonstrate the following. (i) FICZ is formed efficiently by photolysis of Trp upon exposure to visible light. (ii) FICZ is an exceptionally good substrate for cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and its hydroxylated metabolites are remarkably good substrates for the sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally, (iii) sulfoconjugates of phenolic metabolites of FICZ are present in human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators of the AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the widespread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.
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| 12. |
- Bengtsson, Johanna, 1985-, et al.
(author)
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Ketoconazole, omeprazole, and primaquine prolong and enhance the aryl hydrocarbonreceptor signaling induced by the endogenous ligand FICZ
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Other publication (other academic/artistic)abstract
- Several compounds that inhibit cytochrome P4501 (CYP1) enzymes have been shown to actas aryl hydrocarbon receptor (AHR) agonists by reducing the metabolic turnover of the endogenous receptor ligand 6-formylindolo[3,2-b]carbazole (FICZ). In this study we aimed at investigating whether a group of widely prescribed drugs, namely ketoconazole (KTZ),omeprazole (OME) and primaquine (PQ), can act as indirect AHR activators via this mechanism. Inhibitory effects of KTZ, PQ, and OME were measured in CYP1A1 expressing supersomes and all three drugs inhibited CYP1A1 activity. KTZ was the most efficient inhibitor and HPLC analysis revealed that KTZ slowed down the metabolic turnover of intracellular FICZ. All three drugs induced the catalytic activity of CYP1A1 (7-ethoxyresorufin-O-deethylase, EROD) in HaCaT cells as well as increased the expression of CYP1A1 mRNA. Co-exposure to the drugs with FICZ prolonged and enhanced FICZ-induced AHR activation in a synergistic manner. Our findings indicate that KTZ activate AHR by inhibiting the metabolic turnover of FICZ. Interestingly, PQ and OME seem to act by other mechanisms that sensitize the cells to FICZ-dependent transcriptional activation of the AHR.To the author’s knowledge, this is the first publication indicating that KTZ, OME, and PQ can superinduce AHR signaling by increasing the responses to an endogenous receptor ligand.
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| 13. |
- Broberg Palmgren, Karin, et al.
(author)
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Influence of genetic factors on toluene diisocyanate-related symptoms: evidence from a cross-sectional study
- 2008
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In: Environmental Health. - 1476-069X. ; 7:15
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Journal article (peer-reviewed)abstract
- Background: Toluene diisocyanate (TDI) is a highly reactive compound used in the production of, e. g., polyurethane foams and paints. TDI is known to cause respiratory symptoms and diseases. Because TDI causes symptoms in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Methods: Workers (N = 132) exposed to TDI and a non-exposed group ( N = 114) were analyzed for genotype (metabolising genes: CYP1A1*2A, CYP1A1*2B, GSTM1*O, GSTM3*B, GSTP1 1105V, GSTP1 A114V, GSTT1*O, MPO -463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, SULT1A1 R213H; immune-related genes: CCL5 -403, HLA-DQB1* 05, TNF-308, TNF-863) and symptoms of the eyes, upper and lower airways ( based on structured interviews). Results: For three polymorphisms: CYP1A1*2A, CYP1A1*2B, and TNF -308 there was a pattern consistent with interaction between genotype and TDI exposure status for the majority of symptoms investigated, although it did reach statistical significance only for some symptoms: among TDI-exposed workers, the CYP1A1 variant carriers had increased risk (CYP1A1*2A and eye symptoms: variant carriers OR 2.0 95% CI 0.68-6.1, p-value for interaction 0.048; CYP1A1*2B and wheeze: IV carriers OR = 12, 1.4-110, p-value for interaction 0.057). TDI-exposed individuals with TNF-308 A were protected against the majority of symptoms, but it did not reach statistical significance. In the non-exposed group, however, TNF -308 A carriers showed higher risk of the majority of symptoms ( eye symptoms: variant carriers OR = 2.8, 1.1-7.1, p-value for interaction 0.12; dry cough OR = 2.2, 0.69-7.2, p-value for interaction 0.036). Individuals with SULT1A1 213H had reduced risk both in the exposed and non-exposed groups. Other polymorphisms, showed associations to certain symptoms: among TDI-exposed, NAT1*10 carriers had a higher risk of eye symptoms and CCL5 -403 AG+AA as well as HLA-DQB1 *05 carriers displayed increased risk of symptoms of the lower airways. GSTM1, GSTM3 and GSTP1 only displayed effects on symptoms of the lower airways in the non-exposed group. Conclusion: Specific gene-TDI interactions for symptoms of the eyes and lower airways appear to exist. The results suggest different mechanisms for TDI- and non- TDI-related symptoms of the eyes and lower airways.
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| 14. |
- Broberg Palmgren, Karin, et al.
(author)
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The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
- 2010
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In: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 20:2, s. 104-111
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Journal article (peer-reviewed)abstract
- BACKGROUND: Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects. OBJECTIVES: To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine. METHODS: Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H. RESULTS: GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine. CONCLUSION: Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma.
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| 15. |
- Dalene, Marianne, et al.
(author)
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MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulated dose and genotype for N-acetylation
- 1996
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In: International Archives of Occupational and Environmental Health. - 1432-1246. ; 68:3, s. 9-165
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Journal article (peer-reviewed)abstract
- The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 micrograms/l. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (rs = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (rs = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Lind, Monica, et al.
(author)
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Short-term exposure to dioxin impairs bone tissue in male rats
- 2009
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 75:5, s. 680-684
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Journal article (peer-reviewed)abstract
- Chronic and sub-chronic studies in rats have previously shown that dioxin-like compounds impair the bone tissue homeostasis. In the present study, tibiae and serum were analyzed to study possible effects of short term dioxin exposure on rats. Two month old (ca. 200g) male rats were injected with 50microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) kg(-1) bw and tibiae were excised 5d following the exposure. Bone composition, dimensions and strength were analyzed by pQCT and three-point bending test on tibiae. In addition, detailed bone composition was analyzed by optical emission spectroscopy (ICP-OES) and Fourier transform infrared spectrometry (FTIR). Analysis of the serum bone biomarkers procollagen type-I N-terminal propeptide (PINP) and carboxyterminal cross linking teleopeptide (CTX) were also performed. pQCT-results showed alterations in the metaphysis, with a significant decrease in trabecular bone cross-sectional area (-19%, p<0.05) and a significant increase in total bone mineral density (+7%, p<0.05) in TCDD-exposed rats. Analyses of the bones by ICP-OES and FTIR showed that bones from exposed rats had a higher relative proportion of crystalline phosphate (+13% for a1080 and +11% for a1113, p<0.05) and lower acid phosphate content (-22% for a1145, p<0.05), resembling the composition of more mature bones. Serum analysis showed that the bone formation marker PINP was decreased (-37%, p<0.05) and that the bone resorption marker CTX was increased (+14%, p<0.05) indicating a net loss of bone tissue. In conclusion, 5d of exposure to TCDD was sufficient to negatively affect bone tissue in male rats.
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| 20. |
- Rannug, Agneta, 1949-
(author)
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Genotoxic hazards in the rubber industry : application of short-term tests in work environment analyses
- 1984
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Doctoral thesis (other academic/artistic)abstract
- Excess mortality from a number of different types of cancer has been associated with work in the rubber industry. The aim of the present study - using short-term tests for mutagenicity - was to identify potentially hazardous additives and process fumes to which workers are exposed. The study also includes a more detailed investigation of the mechanism by which certain additives of the dithiocarbamate type exert their mutagenic effects. The test materials were provided by Swedish and Finnish rubber manufacturers. Process fumes were collected at a rubber industry or prepared by simulated industrial processing of various rubber formulations in the laboratory. Tests of the individual additives and process fumes were carried out mainly using the Salmo- ne/Za/mammalian microsome test (Ames test) for mutagenicity, with follow-up studies using other test systems for mutagenicity on Drosophila, mammalian cells in culture, and mice. Among 46 additives, 15 compounds, mainly accelerators and antioxidants, were identified as mutagens. 16 compounds were considered non mutagenic and 15 gave results that did not allow any conclusion regarding their possible mutagenic activity. Some dithiocarbamic acid derivatives gave mutagenic effects in more than one test system. The results from the present work indicate that the mutagenicity of dithiocarbamates depends on an indirect action involving oxygen radicals. Interaction with both production and detoxification of reactive forms of oxygen is suggested to be responsible for the mutagneic effects. The usefulness of short-term tests for mutagenicity was also demonstrated by the results from tests of various process vapors. From these tests, it could be concluded that thermal degradation of rubber materials at temperatures used in the industrial processes results in a release of mutagenic factors. In many instances, these were shown to be derived from the rubber polymers. In some cases, contributions from the additives were also shown.
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| 21. |
- Vineis, Paolo, et al.
(author)
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Evidence of gene-gene interactions in lung carcinogenesis in a large pooled analysis
- 2007
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 28:9, s. 1902-1905
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Journal article (peer-reviewed)abstract
- To test the hypothesis of interaction among genetic variants in increasing the individual risk of cancer, we have studied the cumulative effect on lung cancer risk of variants in three metabolic genes, CYP1A1, GSTM1 and GSTT1, which are involved in the metabolism of the tobacco smoke constituents and environmental contaminants, polycyclic aromatic hydrocarbons and of other lung carcinogens. We have selected from the Genetic Susceptibility to Environmental Carcinogens pooled analysis all the studies on lung cancer conducted after 1991 in which all variants were available. The data set includes 611 cases and 870 controls. We found a cumulative effect of the combination of the a priori ' atrisk ' alleles for these genes (P for trend 0.004). The risk of lung cancer was increased with the combination of CYP1A1*2B or CYP1A1*4 alleles and the double deletion of both GSTM1 and GSTT1 up to an odds ratio (OR) of 8.25 (95% confidence interval 2.29-29.77) for the combination including CYP1A1*4; among never smokers, the latter combination was associated with an OR of 16.19 (1.90-137). Estimates did not change after adjustment by the number of cigarettes smoked and duration of smoking were consistent across ethnicities and were approximately the same for adenocarcinomas and squamous cell carcinomas. These observations from a large pooled analysis strongly suggest the existence of gene-gene interactions in lung carcinogenesis. People with rare combinations of common gene variants have a high risk of cancer and can be assimilated to subjects with highly penetrant mutations.
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