Is the activation of aflatoxin B1 catalysed by the same form of cytochrome P-450 as that 4-hydroxylating debrisoquine in rat and/or man?
A possible association between the metabolic activation of aflatoxin B1 (AFB1) to a mutagen and the 4-hydroxylation of debrisoquine, which shows genetic variation both in man and in the rat, was investigated. Hepatic microsomal fractions from female DA and Fischer rats catalyse, at the same rate, the conversion of AFB1 to a mutagenic and arylating metabolite, that bound covalently to microsomal proteins. Debrisoquine was without effect on either of these reactions. In contrast, metyrapone did inhibit the mutagenic activation of AFB1. Microsomal fraction from human liver was also capable of activating AFB1 to a mutagenic and arylating metabolite. Again, debrisoquine was without appreciable effect on these reactions. In contrast, cimetidine caused profound inhibition of the mutagenic activation of AFB1. It is concluded that the activation of AFB1 to a mutagenic, and presumably carcinogenic, metabolite is catalysed by a different form of cytochrome P-450 from that catalysing the 4-hydroxylation of debrisoquine, both in rat and in man.
Plummer
S
S
Boobis
A R
AR
Davies
D S
DS
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009152:Mutagenicity Tests; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects
D000348:Aflatoxins; D007546:Isoquinolines; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D003647:Debrisoquin