title: Differential inhibition of aflatoxin B1 oxidation by gestodene action on human liver microsomes.
abstract: Human cytochrome P450 (P450) 3A is known to be involved in the formation of both aflatoxin B1-exo-8,9-epoxide (exo-epoxidation) and aflatoxin Q1 (3 alpha-hydroxylation). Gestodene, a known inactivator of P450 3A4, inhibited the formation of AFB1 metabolites in a variety of ways depending on the incubation condition. Preincubation of gestodene with human liver microsomes prior to the addition of AFB1 inhibited both exo-epoxidation and 3 alpha-hydroxylation whereas simultaneous incubation of gestodene with AFB1 only inhibited 3 alpha-hydroxylation. These results suggest that two independent substrate binding sites exist in P450 3A4, and AFB1 binds to both of the binding sites. Gestodene selectively binds to one of the binding sites leading to the formation of AFQ1, whereas it does not affect the formation of exo-epoxide via the other binding site.
authors.affiliation: Department of Biochemistry, School of Medicine, Won Kwang University, Iksan, Korea.
authors.forename: B R
authors.initials: BR
authors.lastname: Kim
authors.forename: H S
authors.initials: HS
authors.lastname: Oh
authors.forename: D H
authors.initials: DH
authors.lastname: Kim
mesh_terms: D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009652:Norpregnenes / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D009652:Norpregnenes; C033273:Gestodene; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A