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

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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	Unknown	Inducer	Details

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