Metabolism of Aflatoxin B1 in the Isolated Nuclei of Rat Liver1

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Abstract
The nuclear biotransformation of aflatoxin B 1in vitro was observed with regard to inducer specificity, pH dependency, time course, kinetics, inhibitor sensitivity, and nuclear localization, and these data were compared with those from the micro-somal transformation of aflatoxin B 1 . The nuclei and microsomes are capable of metabolizing aflatoxin B 1 into aflatoxin M 1 , aflatoxin Q 1 , and two unidentified fluorescent compounds in the presence of fortified NADPH generating system. Pretreatments of rats by 3-methylcholanthrene or polychorinated biphenyl enhanced both the nuclear and microsomal C-9α-hydroxylation of aflatoxin B 1 into aflatoxin M 1 and phenobarbital or polychlorinated biphenyl induced aflatoxin Q 1 production. The optimal pHs for aflatoxin M 1 and Q 1 were 8.3 and 7.4, respectively, both in the nuclei and microsomes. Kinetic analysis revealed the Km of aflatoxin M 1 formation in methylcholanthrene-induced nuclei was 9.4 × 10 −5 M, and this value was very close to that obtained with the microsomes. Inhibitor experiments revealed a high sensitivity of aflatoxin M 1 formation to 7,8-benzoflavone and a low sensitivity of aflatoxin Q 1 to SKF 525A. These findings and data on the detergent treatment of nuclei suggest that the nuclear cytochrome P-448 system, induced by 3-methylcholanthrene and localized in the outer membrane, catalyzes the aflatoxin M 1 formation, and the cytochrome P-450 system induced by phenobarbital biotransforms aflatoxin B 1 into aflatoxin Q 1 . Pretreatment of rats by phenobarbital was found to induce microsomal degradation or detoxication of aflatoxin B 1 into water-soluble metabolites, and no such an induction was observed in the nuclei.