The Effect of All-Trans-Retinoic Acid on the Activity and the Gene Expression of Drug Metabolizing Enzymes in Rat Skin

Lee, Ha Rin; Hahm, Jeong Hee; Hong, Young Sook

Abstract

BACKGROUND: The activity of drug metabolizing enzymes and the modulation of their expression by inducers in the skin are the key factors for understanding of pharmacological and toxic effects of topically applied drugs. The role of these enzymes is of major importance, as they may contribute to determine the steady-state levels of biologically active substances. 3-Methylcholanthrene and all-trans- retinoic acid have been known to be inducers of the drug metabolizing enzymes. And all-trans- retinoic acid has many biological actions including anti-cancer effects.
OBJECTIVE
The purpose of this study was to evaluate the effect of all-trans-retinoic acid on inducing the expression and modulation of genetic polymorphism of drug metabolizing enzymes as well as to estimate the role of all-trans-retinoic acid in carcinogenesis and drug interactions.
METHODS
We analyzed the activities of CYP1A1(Cytochrome P450 1Al), NADPH cytochrome P450-reductase, UGT1 and GST after administration of 3-methylcholanthrene and all-trans-retinoic acid to the Sprague-Dawley male rats. We observed the inducible gene expression of CYP1A1, UGT1, GSTJt by RT-PCR and the genetic polymorphism of CYP1A1, UGT1, GSTK by PCR.
RESULTS
1. The expression of CYP1A1, NADPH cytochrome P450-reductase, UGT1 and GST was induced by 3-methylcholanthrene and all-trans-retinoic acid. That of NADPH cytochrome P450-reductase and UGT1 is pronouncedly enhanced by all-trans- retinoic acid. 2. The effects of 3-methylcholanthrene and all-trans-retinoic acid on inducing the expression of CYP1A1 and UGT1 correlated with an increase of mRNA expression levels of CYP1A1 and UGT1. The modulation of mRNA expression levels of GST was downregulated by all-trans-retinoic acid. 3. The genetic polymorphism of CYP1A1 was induced by 3-methylcholanthrene and all-trans- retinoic acid, and that of GSTM1 was not affected by the inducers. The induction of genetic polymorphism of GST was down regulated by all-trans-retinoic acid.
CONCLUSION
3-Methylcholanthrene and all-trans-retinoic acid modulate the inducible expression and genetic polymorphism of drug metabolizing enzymes differentially. All-trans-retinoic acid can modulate the metabolism of procarcinogen such as 3-methylcholanthrene by inducing drug metabolizing enzymes. Furthermore, the elucidation of the molecular mechanisms underlying the regulation of drug metabolizing enzymes by 3-methylcholanthrene, all-trans-retinoic acid and other drugs could help to understand their respective roles in drug interactions and carcinogenesis.