Role of rat cytochromes P450 in the oxidation of 17α-ethinylestradiol

Abstract 17α-Ethinylestradiol (EE2) is an endocrine disruptor (ED) used as an ingredient of oral contraceptives. Rat hepatic microsomes metabolize EE2 to three products; two of them are hydroxylated EE2 derivatives. Of the hydroxylation reactions, 2-hydroxylation, is the major reaction. Cytochrome P450 (CYP) plays a major role in EE2 hydroxylation. To resolve which rat CYPs are responsible for EE2 oxidation, three approaches were used: induction of specific CYPs, selective inhibition of CYPs, and recombinant rat CYPs. The results demonstrate that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. EE2 is also an inhibitor of CYP2C- and CYP3A-catalyzed hydroxylation of endogenous EDs progesterone and testosterone. EE2 acts as a reversible inhibitor of CYP3A-mediated progesterone 6β-hydroxylation and inactivates CYP3A- and CYP2C-catalyzed testosterone 6β-hydroxylation and progesterone 21- or 16α-hydroxylation, respectively, in a mechanism-based manner.