title: The metabolism of 17 alpha-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.
abstract: The metabolism of 17 alpha-ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2-Hydroxyethinyloestradiol (2-OHEE2) was either the sole or principal metabolite. Small amounts of 6-hydroxyethinyloestradiol and 16-hydroxyethinyloestradiol were produced by some of the livers. EE2 (10 microM) underwent substantial (5-20% of incubated drug), though highly variable, NADPH-dependent metabolism to material irreversibly bound to microsomal protein. 2-OHEE2 appeared to be the pro-reactive metabolite. The maximum EE2 2-hydroxylase activity was 0.67 nmol min-1 mg-1 microsomal protein, with a Km value of 8.6 microM. Oestradiol, which is mainly hydroxylated to 2-hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. Progesterone, which undergoes 2-hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. Primaquine was the most potent non-steroidal inhibitor but was non-competitive. Other non-steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2-hydroxylation. The results of this study suggest that EE2 2-hydroxylation is metabolised by a form(s) of cytochrome P-450 which has affinity for endogenous steroids.
mesh_terms: D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D002396:Catechols / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019363:Cytochrome P-450 CYP1A1; D004997:Ethinyl Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016030:Kidney Transplantation; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D011485:Protein Binding; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002396:Catechols; D004997:Ethinyl Estradiol; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C020120:estrogen 2-hydroxylase