Human cytochrome P450 3A7 has a distinct high catalytic activity for the 16α-hydroxylation of estrone but not 17β-estradiol

Like catechol estrogens, 16alpha-hydroxylated estrogens are hormonally active, chemically reactive, and potentially mutagenic. We report here our novel findings that human CYP3A7 has a distinct high catalytic activity for the NADPH-dependent 16alpha-hydroxylation of estrone (E-1; at 10 nm to 200 1 mum substrate concentrations) but not for the 16a-hydroxylation of 17beta-estradiol (E-2). At a physiologically relevant low substrate concentra tion (10 nm), CYP3A7 had a strong catalytic activity for the 16alpha-hydroxylation of E-1, and the ratio of its 16alpha-hydroxylation to 2-hydroxylation was 107%. In addition to 16alpha-hydroxylation, CYP3A7 also had catalytic activity for the 2-, 4-, 6beta-, and 16beta-hydroxylation of E-1. However, when E-2 was the substrate, CYP3A7 had only very weak catalytic activity for its 16alpha-hydroxylation (<6% of E-1 16alpha-hydroxylation), and the ratio of its 16alpha-hydroxylation to 2-hydroxylation was 10-33%. Enzyme kinetic analysis showed that the maximal velocity and substrate-binding affinity (1/K-m) for CYP3A7-mediated 16alpha-hydroxylation of E-1 were both similar to10 times higher than those for E-2, thereby giving the maximal velocity:K-m ratio of >100 times higher for the 16alpha-hydroxylation of El than for E2. Given the recent findings that human CYP3A7 is a polymorphic isoform also expressed in adult liver and certain extrahepatic tissues (in addition to fetal tissues), our data raise the possibility that CYP3A7 may be an important catalyst for the local and/or systemic formation of the procareinogenic 16alpha-hydroxyestrone in women.