DIFFERENTIAL INHIBITION OF AFLATOXIN B-1 OXIDATION BY GESTODENE ACTION ON HUMAN LIVER-MICROSOMES

Human cytochrome P450 (P450) 3A is known to be involved in the formati on of both aflatoxin B-1-exo-8,9-epoxide (exo-epoxidation) and aflatox in Q(1)(3 alpha-hydroxylation). Gestodene, a known inactivator of P450 3A4, inhibited the formation of AFB(1) metabolites in a variety of wa ys depending on the incubation condition. Preincubation of gestodene w ith human liver microsomes prior to the addition of AFB(1) inhibited b oth exo-epoxidation and 3 alpha-hydroxylation whereas simultaneous inc ubation of gestodene with AFB(1) only inhibited 3 alpha-hydroxylation. These results suggest that two independent substrate binding sites ex ist in P450 3A4, and AFB(1) binds to both of the binding sites. Gestod ene selectively binds to one of the binding sites leading to the forma tion of AFQ(1), whereas it does not affect the formation of exo-epoxid e via the other binding site.