Metabolic Basis for Susceptibility and Resistance to Aflatoxin B₁ Hepatocarcinogenesis in Rodents

Abstract

Hepatocarcinogen, aflatoxin B₁ (AFB₁), undergoes metabolic activation via epoxidation and the interaction of this epoxide with DNA is believed to be responsible for its initiation of carcinogenesis. Several in vitro and in vivo studies suggest that epoxidation alone cannot account for differences in AFB₁-DNA binding and carcinogenicity observed in rats (susceptible species) and hamsters (resistant). Recent work from my laboratory on AFB₁ metabolism with hepatocellular fractions and isolated hepatocytes from rats and hamsters has been reviewed. These studies indicate that cytosolic glutathione (GSH) S-transferases play an important role in the modulation of hepatic AFB₁-DNA binding. Inhibition of hepatocarcinogenesis and AFB₁-DNA binding by pretreatment of rats with various inducers are discussed. Even though phenobarbital (PB) is an inducer of both cytochrome P-450 and GSH S-transferases, the subcellular, hepatocyte and in vivo data suggest that induced levels of GSH S-transferases are largely responsible for lower levels of hepatic AFB₁-DNA binding in PB-treated rats. In contrast, the mechanism of inhibition of AFB₁-DNA binding and hepatocarcinogenesis by β-naphthoflavone pretreatment of rats is mediated by stimulation of an inactivation pathway involving cytochrome P-450 dependant oxidative reaction. Finally, data on chemoprevention of AFB₁ hepatocarcinogenesis by pretreatment of rats with various antioxidants suggesting a major role of GSH S-transferases are also reviewed.