Effects of food restriction on the expression of genes related to acetaminophen-induced liver toxicity in rats

抄録

It is well known that fasting substantially affects the metabolism of drugs and chemicals. Food restriction also affects drug kinetics, such as absorption, metabolism, and excretion, and therefore, it can potentially modulate the onset of chemical toxicity or drug-induced adverse reactions. In the present study, the expression of drug-metabolizing enzyme genes and total glutathione content in the liver, which are related to toxicity induced by overdose of the hepatotoxic drug acetaminophen (N-acetyl-p-aminophenol; APAP), were examined in rats reared under different feeding conditions: ad libitum feeding, 16-h fasting, and food restriction (fed 70% of the average intake of ad libitum feeding for 10 days) conditions. The rats under food restriction conditions as well as fasted rats showed significantly higher expression of Cyp2e1, the gene encoding the enzyme that metabolizes APAP to its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). They also had lower levels of liver total glutathione, which detoxifies NAPQI. In contrast, the gene expression of UDP-glucuronosyltransferase 1A6 (Ugt1a6), sulfotransferase 1A1 (Sult1a1), and glutathione S-transferase M1 (Gstm1) was not affected by food restriction or fasting. When APAP was administered (800 mg/kg), histopathological changes were not observed in rats fed ad libitum, while hepatocellular necrosis was observed in most of the rats treated with APAP after fasting or food restriction. Taken together, these results suggest that not only fasting but also food restriction exacerbate APAP-induced acute liver injury, probably by the induction of CYP2E1 and the reduction of liver glutathione contents, in rodents.