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Cutaneous metabolic...
Cutaneous metabolic activation of carvoxime, a self-activating, skin-sensitizing prohapten.
- Article/chapterEnglish2009
Publisher, publication year, extent ...
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2009-01-07
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American Chemical Society (ACS),2009
Numbers
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LIBRIS-ID:oai:gup.ub.gu.se/101573
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https://gup.ub.gu.se/publication/101573URI
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https://doi.org/10.1021/tx8003642DOI
Supplementary language notes
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Bioactivation of low molecular weight compounds in the skin can cause contact sensitization. We have previously shown that the alpha, beta-R-unsaturated oxime R-carvoxime [1, (R)-2-methyl-5-isopropenylcyclohex-2-enone oxime] is bioactivated to two diastereomeric highly reactive and strongly sensitizing alpha, beta-epoxy oxime metabolites. To investigate if this metabolic activation is catalyzed by the major cytochrome P450 (P450) enzymes found in human skin, incubations of 1 with a skinlike P450 cocktail in the presence of glutathione were carried out. We identified three glutathione conjugates in the incubation mixture arising from two diasteomeric alpha, beta-epoxy oxime metabolites of 1, thus showing that the metabolic activation of 1 is P450-mediated. A P450 identification study using the individual P450 enzymes present in the skinlike P450 cocktail showed the involvement of P450 1A1 and 1B1 and also to some extent 2B6. P450 1B1 metabolism of 1 was found to be stereoselective as glutathione conjugates from only one of the alpha, beta-epoxyoxime metabolites were identified (metabolite 2). Additionally, 1 was found to be an inducer of P450 1B1 (but not 1A1) in human monocyte-derived dendritic cells (moDCs) and to some extent in normal human epidermal keratinocytes. A further transcriptional gene expression change observed in moDCs was a 44-fold upregulation of IL-8, a marker often used for assessment of sensitizing potential of contact allergens. The autoinduction of P450 1B1 by 1 may be a key event in the development of contact allergy to 1 and may also explain why only metabolite 2, and not 3, was found to elicit an allergic response in mice sensitized to 1. Our data show that the alpha, beta-unsaturated oxime 1 is bioactivated by human cutaneous P450, thus forming highly allergenic metabolites, and has the potential to induce its own bioactivation pathway, particularly in antigen-presenting cells.
Subject headings and genre
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NATURVETENSKAP Kemi hsv//swe
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NATURAL SCIENCES Chemical Sciences hsv//eng
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Animals
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Cell Line
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Chromatography
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Liquid
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Cyclohexanones
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chemistry
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metabolism
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Cytochrome P-450 Enzyme System
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metabolism
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Dendritic Cells
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drug effects
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Glutathione
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metabolism
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Haptens
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chemistry
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metabolism
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pharmacology
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Humans
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Interleukin-18
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metabolism
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Keratinocytes
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drug effects
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Mass Spectrometry
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Mice
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Microsomes
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Liver
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metabolism
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Oximes
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chemistry
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metabolism
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pharmacology
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Skin
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enzymology
Added entries (persons, corporate bodies, meetings, titles ...)
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Andresen Bergström, Moa,1978Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry(Swepub:gu)xanmoa
(author)
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Heise, Ruth
(author)
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Skazik, Claudia
(author)
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Zwadlo-Klarwasser, Gabriele
(author)
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Merk, Hans F
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Baron, Jens M
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Karlberg, Ann-Therese,1947Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry(Swepub:gu)xkaann
(author)
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Göteborgs universitetInstitutionen för kemi
(creator_code:org_t)
Related titles
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In:Chemical Research in Toxicology: American Chemical Society (ACS)22:2, s. 399-4050893-228X1520-5010
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