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

被引:25
作者
Du, Liping
Neis, Mark M.
Ladd, Patricia A.
Keeney, Diane S.
机构
[1] Vanderbilt Univ, Sch Med, Dept Med Dermatol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA
[3] Rhein Westfal TH Aachen, Univ Hosp, Dept Dermatol & Allergol, D-5100 Aachen, Germany
[4] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA
关键词
HUMAN KERATINOCYTES; AH RECEPTOR; CYTOCHROME P450S; IN-SITU; ACTIVATION; MOUSE; TRANSGLUTAMINASE; PATHWAYS; ENZYMES; DIOXIN;
D O I
10.1124/jpet.106.111724
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Human epidermal keratinocytes express subsets of cytochromes P450 (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 P450s. Real-time polymerase chain reaction (PCR) assays measured CYP1-4 mRNA levels in epidermal keratinocytes differentiated in vitro in the presence of drug or vehicle for 6 days. We confirmed the spinous phenotype at day 6 by changes in cellular morphology and upregulation 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, and 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-tetrachlorodibenzop-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 toward chloracne in humans exposed to toxic levels of dioxin.
引用
收藏
页码:1162 / 1171
页数:10
相关论文
共 40 条
[1]   Cytochrome P450: A target for drug development for skin diseases [J].
Ahmad, N ;
Mukhtar, H .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2004, 123 (03) :417-425
[2]   Mouse liver CYP2C39 is a novel retinoic acid 4-hydroxylase - Its down-regulation offers a molecular basis for liver retinoid accumulation and fibrosis in aryl hydrocarbon receptor-null mice [J].
Andreola, F ;
Hayhurst, GP ;
Luo, G ;
Ferguson, SS ;
Gonzalez, FJ ;
Goldstein, JA ;
De Luca, LM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (05) :3434-3438
[3]   Function and regulation of AP-1 subunits in skin physiology and pathology [J].
Angel, P ;
Szabowski, A ;
Schorpp-Kistner, M .
ONCOGENE, 2001, 20 (19) :2413-2423
[4]  
[Anonymous], CLIN MICROBIOL IN S1
[5]   Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro [J].
Baron, JM ;
Heise, R ;
Blaner, WS ;
Neis, M ;
Joussen, S ;
Dreuw, A ;
Marquardt, Y ;
Saurat, JH ;
Merk, HF ;
Bickers, DR ;
Jugert, FK .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2005, 125 (01) :143-153
[6]   INTERACTIVE EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN AND RETINOIDS ON PROLIFERATION AND DIFFERENTIATION IN CULTURED HUMAN KERATINOCYTES - QUANTIFICATION OF CROSS-LINKED ENVELOPE FORMATION [J].
BERKERS, JAM ;
HASSING, I ;
SPENKELINK, B ;
BROUWER, A ;
BLAAUBOER, BJ .
ARCHIVES OF TOXICOLOGY, 1995, 69 (06) :368-378
[7]   Ah receptor:: Dioxin-mediated toxic responses as hints to deregulated physiologic functions [J].
Bock, Karl Walter ;
Koehle, Christoph .
BIOCHEMICAL PHARMACOLOGY, 2006, 72 (04) :393-404
[8]  
CROW KD, 1991, DERMATOTOXICOLOGY
[9]   Effects of the differentiated keratinocyte phenotype on expression levels of CYP1-4 family genes in human skin cells [J].
Du, Liping ;
Neis, Mark M. ;
Ladd, Patricia A. ;
Lanza, Diane L. ;
Yost, Garold S. ;
Keeney, Diane S. .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2006, 213 (02) :135-144
[10]   Molecular mechanisms of retinoid actions in skin [J].
Fisher, GJ ;
Voorhees, JJ .
FASEB JOURNAL, 1996, 10 (09) :1002-1013