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STEREO- AND REGIOSELECTIVITY ACCOUNT FOR THE DIVERSITY OF DEHYDROEPIANDROSTERONE (DHEA) METABOLITES PRODUCED BY LIVER MICROSOMAL CYTOCHROMES P450

Departments of Biochemistry and Molecular Biology (K.K.M.M., S.L.R., R.A.P.) and Pharmacology and Toxicology (J.C., W.M.P.), University of Louisville School of Medicine, Louisville, Kentucky; and the Merck Research Laboratory, West Point, Pennsylvania (T.H.R.)

The purpose of this study was to quantify the oxidative metabolism of dehydroepiandrosterone (3ß-hydroxy-androst-5-ene-17-one; DHEA) by liver microsomal fractions from various species and identify the cytochrome P450 (P450) enzymes responsible for production of individual hydroxylated DHEA metabolites. A gas chromatography-mass spectrometry method was developed for identification and quantification of DHEA metabolites. 7-Hydroxy-DHEA was the major oxidative metabolite formed by rat (4.6 nmol/min/mg), hamster (7.4 nmol/min/mg), and pig (0.70 nmol/min/mg) liver microsomal fractions. 16-Hydroxy-DHEA was the next most prevalent metabolite formed by rat (2.6 nmol/min/mg), hamster (0.26 nmol/min/mg), and pig (0.16 nmol/min/mg). Several unidentified metabolites were formed by hamster liver microsomes, and androstenedione was produced only by pig microsomes. Liver microsomal fractions from one human demonstrated that DHEA was oxidatively metabolized at a total rate of 7.8 nmol/min/mg, forming 7-hydroxy-DHEA, 16-hydroxy-DHEA, and a previously unidentified hydroxylated metabolite, 7ß-hydroxy-DHEA. Other human microsomal fractions exhibited much lower rates of metabolism, but with similar metabolite profiles. Recombinant P450s were used to identify the cytochrome P450s responsible for DHEA metabolism in the rat and human. CYP3A4 and CYP3A5 were the cytochromes P450 responsible for production of 7-hydroxy-DHEA, 7ß-hydroxy-DHEA, and 16-hydroxy-DHEA in adult liver microsomes, whereas the fetal/neonatal form CYP3A7 produced 16-hydroxy and 7ß-hydroxy-DHEA. CYP3A23 uniquely formed 7-hydroxy-DHEA, whereas other P450s, CYP2B1, CYP2C11, and CYP2D1, were responsible for 16-hydroxy-DHEA metabolite production in rat liver microsomal fractions. These results indicate that the stereo- and regioselectivity of hydroxylation by different P450s account for the diverse DHEA metabolites formed among various species.

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