Role of human cytochrome P450 1A1, IA2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17 beta-estradiol

The steady-state kinetics and specific activity of 2-, 4-, and 16 alpha -hy droxylation of 17 beta -estradiol (E-2) were evaluated for human cytochrome P450 (CYP) 1A1, 1A2, 1B1, and 3A4 enzymes, using complementary DNA-express ed CYP isoforms. CYP1A2 showed the highest 2-hydroxylation activity, follow ed by CYP1A1, 1B1, and 3A4. CYP1B1 had the highest 4-hydroxylation activity , followed by CYP1A2, 1A1, and 3A4. The 16 alpha -hydroxylation reaction wa s catalyzed mainly by CYP1A2 and, to a similar, slightly lower extent, CYP3 A4 and 1A1, with a lesser contribution by CYP1B1. The E-2 2-, 4-, and 16 al pha -hydroxylation activities of human liver microsomes were 1.3 +/- 0.3, 0 .5 +/- 0.06, and 0.3 +/- 0.05 nmol metabolite/min/nmol P450, respectively. The contribution of CYP1A1 and 1B1 (mainly extrahepatic) to the E-2 hydroxy lation reactions, relative to CYP1A2 and 3A4 (predominantly hepatic), may b e relevant to understanding the process of hormonal carcinogenesis both in liver and in extrahepatic tissues. Copyright (C) 2001 by W.B. Saunders Comp any.