Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.
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Baron JM, Holler D, Schiffer R, Frankenberg S, Neis M, Merk HF, Jugert FK
Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.
J Invest Dermatol. 2001 Apr;116(4):541-8. doi: 10.1046/j.1523-1747.2001.01298.x.
- PubMed ID
- 11286621 [ View in PubMed]
- Abstract
Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dexamethasone Cytochrome P450 1A1 Protein Humans UnknownInhibitorInducerDetails Dexamethasone Cytochrome P450 2B6 Protein Humans UnknownInducerDetails Dexamethasone Cytochrome P450 2E1 Protein Humans UnknownInducerDetails Dexamethasone acetate Cytochrome P450 1A1 Protein Humans UnknownInhibitorInducerDetails Dexamethasone acetate Cytochrome P450 2B6 Protein Humans UnknownInducerDetails Dexamethasone acetate Cytochrome P450 2E1 Protein Humans UnknownInducerDetails