| 1. |
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| 2. |
- Andersch-Björkman, Ylva, et al.
(författare)
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Air-oxidized linalool elicits eczema in allergic patients-a repeated open application test study.
- 2014
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Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 70:3, s. 129-38
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Tidskriftsartikel (refereegranskat)abstract
- Linalool is a commonly used fragrance terpene that forms potent sensitizers upon oxidation. In a recent multicentre study, we found that 7% of 2900 patients showed positive patch test reactions to oxidized linalool at 6.0%. No elicitation studies have been performed.
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| 3. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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A skin-like cytochrome P450 cocktail activates prohaptens to contact allergenic metabolites.
- 2007
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Ingår i: The Journal of investigative dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 127:5, s. 1145-53
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Tidskriftsartikel (refereegranskat)abstract
- Allergic contact dermatitis is a complex syndrome representing immunological responses to cutaneous exposure to protein-reactive chemicals. Although many contact sensitizers directly can elicit this disorder, others (prohaptens) require activation. Knowledge regarding the activating mechanisms remains limited, but one possibility is metabolic activation by cytochrome P450 (CYP) enzymes in the skin. We have, after quantitative reverse transcriptase-PCR studies of the CYP content in 18 human skin samples, developed an enriched skin-like recombinant human (rh) CYP cocktail using CYP1A1, 1B1, 2B6, 2E1, and 3A5. To validate the rhCYP cocktail, a prohaptenic conjugated diene ((5R)-5-isopropenyl-2-methyl-1-methylene-2-cyclohexene) was investigated using: the skin-like rhCYP cocktail, a liver-like rhCYP cocktail, single rhCYP enzymes, liver microsomes, keratinocytes, and a dendritic cell (DC) assay. The diene was activated to sensitizing epoxides in all non-cell-based incubations including the skin-like rhCYP cocktail. An exocyclic epoxide metabolite ((7R)-7-isopropenyl-4-methyl-1-oxaspiro[2.5]oct-4-ene) was found to be mainly responsible for the allergenic activity of the diene. This epoxide also induced pronounced DC activation indicated by upregulation of IL-8. The skin-like rhCYP cocktail provides a simplified alternative to using skin tissue preparations in mechanistic studies of CYP-mediated skin metabolism of prohaptens and offers the future possibility of designing in vitro predictive assays for assessment of allergenic activity of prohaptens.
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| 4. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.
- 2006
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 19:6, s. 760-9
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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.
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| 5. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Metabolic epoxidation of an alpha,beta-unsaturated oxime generates sensitizers of extreme potency. Are nitroso intermediates responsible?
- 2007
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 20:6, s. 927-936
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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.
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| 6. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Oximes: Metabolic Activation and Structure−Allergenic Activity Relationships
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:8, s. 2541-2550
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure−allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure−allergenic activity relationships found were that an α,β-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.
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| 7. |
- Bråred Christensson, Johanna, 1965, et al.
(författare)
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Fragrance Allergens, Overview with a Focus on Recent Developments and Understanding of Abiotic and Biotic Activation
- 2016
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Ingår i: Cosmetics. - : MDPI AG. - 2079-9284. ; 3:2, s. 19-37
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Tidskriftsartikel (refereegranskat)abstract
- Fragrances and fragranced formulated products are ubiquitous in society. Contact allergies to fragrance chemicals are among the most common findings when patch-testing patients with suspected allergic contact dermatitis, as well as in studies of contact allergy in the general population. The routine test materials for diagnosing fragrance allergy consist mainly of established mixes of fragrance compounds and natural extracts. The situation is more complex as several fragrance compounds have been shown to be transformed by activation inside or outside the skin via abiotic and/or biotic activation, thus increasing the risk of sensitization. For these fragrance chemicals, the parent compound is often non-allergenic or a very weak allergen, but potent sensitizers will be formed which can cause contact allergy. This review shows a series of fragrance chemicals with well-documented abiotic and/or biotic activation that are indicative and illustrative examples of the general problem. Other important aspects include new technologies such as ethosomes which may enhance both sensitization and elicitation, the effect on sensitization by the mixtures of fragrances found in commercial products and the effect of antioxidants. A contact allergy to fragrances may severely affect quality of life and many patients have multiple allergies which further impact their situation. Further experimental and clinical research is needed to increase the safety for the consumer.
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| 8. |
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| 9. |
- Bråred Christensson, Johanna, 1965, et al.
(författare)
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Limonene hydroperoxide analogues differ in allergenic activity
- 2008
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 59:6, s. 344-352
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Tidskriftsartikel (refereegranskat)abstract
- Background: The fragrance terpene R-limonene is a very weak sensitizer but forms allergenic oxidation products upon contact with air. Oxidized (ox.) limonene is a frequent cause of contact allergy in clinical testing. Objectives: This study investigates the sensitizing potencies of ox. and non-ox. limonene and of structurally closely related limonene hydroperoxides. The clinical importance of the difference in sensitizing potency of two hydroperoxides in autoxidized limonene was studied. Patients/Methods: Ox. and non-ox. limonene were investigated in the murine local lymph node assay (LLNA). Limonene hydroperoxides were investigated using a modified LLNA involving non-pooled lymph nodes and statistical calculations; patch testing of patients with known contact allergy to ox. limonene was performed. Results: A marked increase in the sensitizing potency of ox. limonene compared with that of pure limonene was observed in the LLNA. One analogue, limonene-1-hydroperoxide, was a significantly more potent sensitizer than the other hydroperoxides and gave more positive test reactions in the allergic patients. Conclusions: The results support that hydroperoxides have a specific reactivity indicating that oxygen-centred radicals are important in hapten–protein complex formation of hydroperoxides. The primary oxidation products of ox. limonene, the hydroperoxides, have an important impact on the sensitizing capacity of the oxidation mixture.
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| 10. |
- Bråred Christensson, Johanna, 1965, et al.
(författare)
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Limonene hydroperoxide analogues show specific patch test reactions.
- 2014
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Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 70:5, s. 291-299
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Tidskriftsartikel (refereegranskat)abstract
- The fragrance terpene R-limonene is a very weak sensitizer, but forms allergenic oxidation products upon contact with air. The primary oxidation products of oxidized limonene, the hydroperoxides, have an important impact on the sensitizing potency of the oxidation mixture. One analogue, limonene-1-hydroperoxide, was experimentally shown to be a significantly more potent sensitizer than limonene-2-hydroperoxide in the local lymph node assay with non-pooled lymph nodes.
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