Genetic expression of aflatoxin metabolism. Effects of 3-methylcholanthrene and beta-naphthoflavone on hepatic microsomal metabolism and mutagenic activation of aflatoxins.
The effects of pretreatment with 3-methylcholanthrene (MC) and beta-naphthoflavone (beta NF) on the hepatic microsome-mediated mutagenesis of aflatoxin B1 (AFB1) and benzo[a]pyrene, and on the metabolism of aflatoxins B1 and B2, were investigated in inbred mouse strains. The inbred strains of mice studied included Ah nonresponsive strains (DBA/2Ha, AKR/Sn and RF/J), which were also nonresponsive to the induction of the metabolism of AFB1 to AFM1 (AFB1-4-hydroxylase activity), and Ah responsive strains (C57BL/6Ha, ICR/Ha, C3H/St, A/St, Balb/cCr, C57e/Ha and CBA/Pi), which were also responsive to the induction of AFB1-4-hydroxylase activity. The hepatic microsome-mediated enzyme activities studied included: mutagenic activation of AFB1 and benzo[a]pyrene in the Ames Salmonella typhimurium TA-98 system; metabolism of AFB1 and AFB2 to AFM1 and AFM2, respectively; and benzo[a]pyrene metabolism measured as the formation of fluorescent phenolic metabolites, i.e. aryl hydrocarbon hydroxylase (AHH) activity. Time-course and dose-response studies in C57BL/6Ha mice revealed that the metabolism of aflatoxin B1/B2 to aflatoxin M1/M2 (AFB1/B2-4-hydroxylase activity) was induced by both MC and beta NF. In the nonresponsive strains studied, pretreatment with MC or beta NF produced essentially little alteration of AFB1-4-hydroxylase activity or AHH activity or the mutagenic activation of AFB1 and benzo[a]pyrene. On the other hand, AFB1-4-hydroxylase activity in the responsive strains was induced 4- to 10-fold by MC (60 mg/kg) and 2.5- to 7-fold by beta NF (150 mg/kg). Also in the responsive strains, induction of AFB1-4-hydroxylase activity was strongly associated with (a) the depression of the mutagenic activation of AFB1, and (b) with the induction of both AHH and the mutagenic activation of benzo[a]pyrene. In summary, the results described in this report suggest that: (a) induction of AFB1-4-hydroxylase activity by MC (or beta NF) is associated with the depression of AFB1 mutagenesis and with the induction of benzo[a]pyrene mutagenesis; and (b) induction by MC (or beta NF) of AHH activity, AFB1-4-hydroxylase activity and AFB2-4-hydroxylase activity is controlled by either the same or closely linked genetic factors.
D000348:Aflatoxins / Q000378:metabolism*; D000818:Animals; D001564:Benzo(a)pyrene; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000235:genetics; D019324:beta-Naphthoflavone
D000348:Aflatoxins; D001571:Benzoflavones; D001580:Benzopyrenes; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D006899:Mixed Function Oxygenases; C019623:aflatoxin B1 hydroxylase