Regulation of cutaneous drug-metabolizing enzymes and cytoprotective gene expression by topical drugs in human skin in vivo.
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Smith G, Ibbotson SH, Comrie MM, Dawe RS, Bryden A, Ferguson J, Wolf CR
Regulation of cutaneous drug-metabolizing enzymes and cytoprotective gene expression by topical drugs in human skin in vivo.
Br J Dermatol. 2006 Aug;155(2):275-81.
- PubMed ID
- 16882163 [ View in PubMed]
- Abstract
BACKGROUND: Individuality in the expression and regulation of hepatic drug-metabolizing enzymes (DMEs) and cytoprotective (CP) genes is an important determinant of treatment response. There is increasing evidence that many DMEs and CP genes are also expressed in human skin. Responses to topical drugs used to treat common skin diseases, such as psoriasis, are unpredictable and may potentially be rationalized, at least in part, by interindividual differences in cutaneous DME and CP gene expression. OBJECTIVES: We investigated whether three topical drugs [coal tar, all-trans retinoic acid (atRA) and clobetasol 17-propionate] used in routine clinical practice modulated the expression of a variety of DME and CP genes [cytochrome P450s, glutathione S-transferases (GSTs) and drug transporters] in healthy human skin in vivo. METHODS: Healthy adult volunteers (n = 30) were invited to participate in the study. Each subject was randomly allocated to receive two of the three study chemicals and one control site application. Crude coal tar (n = 13), atRA (n = 14) or clobetasol 17-propionate (n = 10) was applied under occlusion to photoprotected buttock skin for 96 h. A vehicle control (white soft paraffin) was also applied under the same conditions at an adjacent site in all subjects. Full-thickness punch biopsies (4-mm diameter) were then taken from treated and control sites. Total RNA was extracted and reverse transcribed into cDNA, which was used as a template in subsequent real-time polymerase chain reaction analysis, where fluorescent output was directly proportional to input cDNA concentration. Triplicate measurements of skin mRNA expression were made from each sample, and the arithmetic mean values taken. After logarithmic transformation, the paired t-test was used to compare values between treated and control skin. RESULTS: Cytochrome P450s CYP1A1, CYP1A2, CYP1B1, CYP2C18, quinone reductase (NQO-1), GSTP1, gamma-glutamyl cysteine synthetase (gamma-GCS), glutathione peroxidase-1 (GPx-1), cyclooxygenase-2 (COX-2) and haem oxygenase-1 (HO-1) were induced by coal tar; CYP26, NADPH P450 reductase (CPR), GSTP1 and HO-1 by atRA; and CYP3A5 by clobetasol 17-propionate. In contrast, CYP1A1 and CYP1A2 expression was suppressed by atRA, and gamma-GCS and MRP1 by clobetasol 17-propionate. Marked interindividual variation in gene regulation by topical drugs was seen for the majority of genes examined. CONCLUSIONS: These data demonstrate that topical drugs can modulate DME gene expression in human skin in vivo and indicate that variation in the expression and regulation of these genes may be a determinant of individuality in response to topical therapies for common skin diseases.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Clobetasol propionate Cytochrome P450 3A5 Protein Humans UnknownInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Clobetasol Approved Experimental Investigational ABCC1 4363 downregulated Clobetasol results in decreased expression of ABCC1 mRNA 16p13.11 Clobetasol Approved Experimental Investigational CYP3A5 1577 upregulated Clobetasol results in increased expression of CYP3A5 mRNA 7q22.1 Clobetasol Approved Experimental Investigational GCLC 2729 downregulated Clobetasol results in decreased expression of GCLC mRNA 6p12.1 Coal tar Approved CYP1A1 1543 upregulated Coal Tar results in increased expression of CYP1A1 mRNA 15q24.1 Coal tar Approved CYP1A2 1544 upregulated Coal Tar results in increased expression of CYP1A2 mRNA 15q24.1 Coal tar Approved CYP1B1 1545 upregulated Coal Tar results in increased expression of CYP1B1 mRNA 2p22.2 Coal tar Approved CYP2C18 1562 upregulated Coal Tar results in increased expression of CYP2C18 mRNA 10q23.33 Coal tar Approved GCLC 2729 upregulated Coal Tar results in increased expression of GCLC mRNA 6p12.1 Coal tar Approved GPX1 2876 upregulated Coal Tar results in increased expression of GPX1 mRNA 3p21.31 Coal tar Approved GSTP1 2950 upregulated Coal Tar results in increased expression of GSTP1 mRNA 11q13.2 Coal tar Approved HMOX1 3162 upregulated Coal Tar results in increased expression of HMOX1 mRNA 22q12.3 Coal tar Approved NQO1 1728 upregulated Coal Tar results in increased expression of NQO1 mRNA 16q22.1 Coal tar Approved PTGS2 5743 upregulated Coal Tar results in increased expression of PTGS2 mRNA 1q31.1 Tretinoin Approved Investigational Nutraceutical CYP1A1 1543 downregulated Tretinoin results in decreased expression of CYP1A1 mRNA 15q24.1 Tretinoin Approved Investigational Nutraceutical CYP1A2 1544 downregulated Tretinoin results in decreased expression of CYP1A2 mRNA 15q24.1 Tretinoin Approved Investigational Nutraceutical CYP26A1 1592 upregulated Tretinoin results in increased expression of CYP26A1 mRNA 10q23.33 Tretinoin Approved Investigational Nutraceutical GSTP1 2950 upregulated Tretinoin results in increased expression of GSTP1 mRNA 11q13.2 Tretinoin Approved Investigational Nutraceutical HMOX1 3162 upregulated Tretinoin results in increased expression of HMOX1 mRNA 22q12.3 Tretinoin Approved Investigational Nutraceutical POR 5447 upregulated Tretinoin results in increased expression of POR mRNA 7q11.23