Abstract
Previous studies have demonstrated that pretreatment of rats with butylated hydroxyanisole (BHA) inhibited aflatoxin B1 (AFB1)-DNA binding and AFB1 hepatocarcinogenesis. Our detailed studies on the effect of BHA pretreatment of rats on both AFB1-DNA binding and AFB1-glutathione (AFB1-SG) conjugation with hepatosubcellular fractions, isolated hepatocytes and in intact animals are reviewed. For these studies, young male rats were fed a semisynthetic diet with or without 0.75% BHA for 2 wks. Even though there were no significant differences either in microsomal cytochrome P-450 content or microsome-mediated AFB1 binding to exogenous DNA with cytochrome P-450 from control or treated rats, there were large differences in GSH S-transferase activity with treated cytosols showing 100% higher activity than the controls. Kinetics of cytosolic inhibition of microsome-mediated AFB1-DNA binding and formation of AFB1-SG conjugate indicated that the inhibition of AFB1-DNA binding was greater with cytosols from treated compared to the controls with the concomitant formation of AFB1-SG conjugate. Reconstitution studies with intact nuclei, microsomes and cytosol indicated more AFB1-DNA binding with the control than with BHA-treated animals. In isolated hepatocyte system, at 2 μM level of AFB1, AFB1-DNA binding in treated hepatocytes was about 15% of controls whereas thiol conjugation was 5 fold higher in the treated than in control hepatocytes. Addition of 1 mM styrene oxide caused about 100% and 9 fold increase in AFB1-DNA binding in control and treated hepatocytes respectively with corresponding decreases in thiol conjugation. In intact rats, BHA treatment reduced hepatic AFB1-DNA binding to 15% of controls with concomitant increase in biliary excretion of AFB1-SG conjugate. These results indicate that the induced cytosolic GSH S-transferases after BHA treatment of rats play a significant role in inhibiting hepatic AFB1-DNA binding and AFB1 hepatocarcinogenesis by inactivation of the reactive AFB1-epoxide.
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