Genetic expression of aflatoxin metabolism: Effects of 3-methylcholanthrene and β-naphthoflavone on hepatic microsomal metabolism and mutagenic activation of aflatoxins

Abstract

The effects of pretreatment with 3-methylcholanthrene (MC) and β-naphthoflavone (ßNF) on the hepatic microsome-mediated mutagenesis of aflatoxin B 1 (AFB 1) and benzo[ a]pyrene, and on the metabolism of aflatoxins B 1 and B 2, were investigated in inbred mouse strains. The inbred strains of mice studied included Ah nonresponsibe strains (DBA/2Ha, AKR/Sn and RF/J), which were also nonresponsive to the induction of the metabolism of AFB 1 to AFM 1 (AFB 1-4-hydroxylase activity), and Ah responsive strains (C57BL/6Ha, ICR/Ha, CSH/St, A/St, Balb/cCr, C57e/Ha and CBA/Pi), which were also responsive to the induction of AFBi-4-hydroxylase activity. The hepatic microsome-mediated enzyme activities studied included: mutagenic activation of AFB 1 and benzo[a]pyrene in the Ames Salmonella typhimurium TA-98 system; metabolism of AFB 1 and AFB 2 to AFM 1 and AFM 2, respectively; and benzo[ ya]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 B 1/B 2 to aflatoxin M 1/M 2 (AFB 1/B 2-4-hydroxylase activity) was induced by both MC and ßNF. In the nonresponsive strains studied, pretreatment with MC or ßNF produced essentially little alteration of AFBi-4-hydroxylase activity or AHH activity or the mutagenic activation of AFB 1 and benzo[ a]pyrene. On the other hand, AFB 1-4-hydroxylase activity in the responsive strains was induced 4- to 10-fold by MC (60 mg/kg) and 2.5- to 7-fold by ßNF (150 mg/kg). Also in the responsive strains, induction of AFB 1-4-hydroxylase activity was strongly associated with (a) the depression of the mutagenic activation of AFB 1, 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 AFBi-4-hydroxylase activity by MC (or ßNF) is associated with the depression of AFB 1 mutagenesis and with the induction of benzo[ a]pyrene mutagenesis; and (b) induction by MC (or ßNF) of AHH activity, AFB 1-4-hydroxylase activity and AFB 2-4-hydroxylase activity is controlled by either the same or closely linked genetic factors.