Received for publication August 8, 2006.
Revised September 14, 2006.
Accepted for publication September 15, 2006.

Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classical aryl hydrocarbon receptor ligands

Abstract

Human epidermal keratinocytes express subsets of cytochromes P450 (CYP gene products) that are strongly up-regulated, not regulated, or down-regulated by differentiation-specific factors. We investigated how drug exposure affects epidermal expression of CYP1-4 genes, which encode many drug metabolizing CYPs. Real-time PCR assays measured CYP1-4 mRNA levels in epidermal keratinocytes differentiated in vitro in the presence of drug or vehicle for six days. We confirmed the spinous phenotype at Day 6 by changes in cellular morphology and up-regulation of cytokeratin 10 and transglutaminase (TGM) 1 mRNA in the differentiating keratinocytes. Effects of drug exposure depended on the influence of differentiation-specific factors in controlling epidermal CYP1-4 expression. CYP2C18, 2C19, 2C9, 2W1, 3A4, and 4B1 are up-regulated by cellular differentiation; mRNA levels for these CYP genes were inhibited in differentiating keratinocytes exposed to retinoic acid and aryl hydrocarbon receptor (AhR) ligands. These same drugs effected 2-fold change or even augmented mRNA levels for CYP genes that are not regulated by differentiation (CYP2S1, 2J2, 1B1, 1A1, 1A2, 2E1, 2D6) and for CYP2U1, which is expressed at highest levels in undifferentiated keratinocytes. The clinically relevant drugs miconazole, dexamethasone, rifampicin, and dapsone had little effect on CYP1-4 mRNA levels under assay conditions. The AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin also up-regulated keratinocyte TGM1 mRNA in a concentration- and time-dependent manner. This effect was blocked by the AhR antagonist resveratrol. These findings implicate AhR-dependent up-regulation of TGM1 mRNA in differentiating keratinocytes as one mechanism contributing towards chloracne in humans exposed to toxic levels of dioxin.

Key words: CYP, cytochrome P450, drug metabolism, epithelial cell, keratinocyte, skin

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