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A skin-like cytochrome P450 cocktail activates prohaptens to contact allergenic metabolites.

Andresen Bergström, Moa, 1978 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
Ott, Hagen (author)
Carlsson, Anna (author)
Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
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Neis, Mark (author)
Zwadlo-Klarwasser, Gabriele (author)
Jonsson, Charlotte A, 1971 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
Merk, Hans F (author)
Karlberg, Ann-Therese, 1947 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
Baron, Jens M (author)
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 (creator_code:org_t)
Elsevier BV, 2007
2007
English.
In: The Journal of investigative dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 127:5, s. 1145-53
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

Allergens
immunology
metabolism
Animals
Biotransformation
physiology
Cells
Cultured
Cytochrome P-450 Enzyme System
physiology
Dendritic Cells
cytology
metabolism
Dermatitis
Allergic Contact
immunology
metabolism
Female
Haptens
immunology
metabolism
Humans
Interleukin-8
genetics
metabolism
Keratinocytes
cytology
metabolism
Male
Mice
Mice
Inbred Strains
Microsomes
Liver
enzymology
RNA
Messenger
genetics
metabolism
Skin
enzymology
immunology
Up-Regulation

Publication and Content Type

ref (subject category)
art (subject category)

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