The influence of fasting on the susceptibility of mice to hepatotoxic injury

The hepatotoxic effects of eight compounds as determined by serum activities of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and sorbitol dehydrogenase (SDH) were investigated in normally fed mice on the one hand and 24-hr-fasted mice on the other. Fasting strongly enhanced serum-enzyme elevations induced by carbon tetrachloride, paracetamol, thioacetamide, and bromobenzene. The hepatotoxic effects of phalloidin and allyl alcohol were only moderately increased by fasting and those of α-amanitin and praseodymium not at all. The fasting-induced aggravation of CCl₄ hepatotoxicity (evidenced also by histological findings) appeared already after 12 hr and was maximal after 24 hr of food deprivation. Fasting for 24 hr decreased the liver weight by 29%, hepatic glycogen by 93%, and hepatic glutathione (GSH) by 50% but increased liver triglycerides by 162%. Aniline hydroxylase and aminopyrine N-demethylase activities were higher in the liver homogenate supernatants from fasted than from fed mice but microsomal protein content as well as microsomal NADPH-cytochrome c-reductase activity remained unchanged and microsomal cytochrome P-450 content even decreased upon fasting. Fasting did not influence the in vitro irreversible binding of ¹⁴CCl₄ and ³H]paracetamol to hepatic microsomal proteins nor the in vivo binding to hepatic proteins of ³H]paracetamol. It enhanced, however, the total concentration of ¹⁴CCl₄ in the liver by 30% and produced a trend toward higher values in the extent of ¹⁴CCl₄ bound in vivo to hepatic protein. Spontaneous and CCl₄-induced lipid peroxidation were the same in hepatic microsomes from fed and fasted mice. No unique explanation can be made for the increased susceptibility of mouse liver to toxic injury induced by fasting. Several factors must be considered: depletion of both hepatic glycogen and glutathione as well as hepatic lipid accumulation. Overnight fasting of mice (and of other small animals presumably too) may change the results of toxicological experiments to an unpredictable degree and should thus be avoided.