To assess modification of
thioacetamide-induced hepatotoxicity in mice fed a high-fat diet, male C57BL/6J mice were fed a normal rodent diet or a high-fat diet for 8 weeks and then treated once intraperitoneally with
thioacetamide at 50 mg/kg
body weight. At 24 and 48 hours after administration, massive centrilobular hepatocellular
necrosis was observed in mice fed the normal rodent diet, while the
necrosis was less severe in mice fed the high-fat diet. In contrast, severe swelling of hepatocytes was observed in mice fed the high-fat diet. In addition, mice fed the high-fat diet displayed more than a 4-fold higher number of
BrdU-positive hepatocytes compared with mice fed the normal rodent diet at 48 hours after
thioacetamide treatment. To clarify the mechanisms by which the hepatic
necrosis was attenuated, we investigated exposure to
thioacetamide and one of its metabolites, the expression of
CYP2E1, which converts
thioacetamide to reactive metabolites, and the content of
glutathione S-
transferases in the liver. However, the reduced hepatocellular
necrosis noted in mice fed the high-fat diet could not be explained by the differences in exposure to
thioacetamide or
thioacetamide sulfoxide or by differences in the expression of
drug-metabolizing
enzymes. On the other hand, at 8 hours after
thioacetamide administration, hepatic total
glutathione in mice fed the high-fat diet was significantly lower than that in mice fed the normal diet. Hence, decreased hepatic
glutathione amount is a candidate for the mechanism of the attenuated
necrosis. In conclusion, this study revealed that
thioacetamide-induced hepatic
necrosis was attenuated in mice fed the high-fat diet.