16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5

Carcinogenesis
Z HuangL S Kaminsky

Abstract

The cytochrome P450 (P450) enzymes that catalyse metabolism of the estrogen, estrone (E1), to the putative carcinogen 16alpha-hydroxy E1 (16alpha-OHE1) in humans were determined. The potential of the most abundant circulating form of estrogen, estrone 3-sulfate (E1S), to be the substrate was also investigated. Human liver microsomal sulfatases convert E1S to E1, an essential prerequisite for formation of 16alpha-OHE1 from added E1S in this system. E1 metabolism to 16alpha-OHE1 in a panel of 15 human liver microsomal preparations correlated with total P450 concentrations (r2 = 0.63) and with activities associated with P450 forms CYP3A4 and 3A5 (r2 = 0.72). E1 16alpha-hydroxylase activity in human liver microsomes was inhibited by 75% by monoclonal anti human CYP3A4/5 antibodies at 4 mg antibody/nmol total P450, and by troleandomycin, a specific CYP3A4/5 inhibitor. Rates of E1 metabolism to 16alpha-OHE1 were 1.6-fold higher when E1 was generated in situ from E1S than when E1 was added. Microsomal preparations of cDNA expressed CYP3A4 or 3A5, with NADPH-P450-reductase co-expressed, both metabolized E1 to 16alpha-OHE1, and added cytochrome b5 increased the rates 5.1- and 7.5-fold, respectively. In these systems rates of E1 metaboli...Continue Reading

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