Acetaminophen toxicity in fed and fasted mice

Abstract

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.

UDP-Glucuronosyltransferase Expression in Mouse Liver Is Increased in Obesity- and Fasting-Induced Steatosis

“…However, it is also known that fasting decreases the rate of protein synthesis and increases protein degradation in mammalian animal models (Cherel et al, 1991), which subsequently decreases the cellular protein levels described by decreased UGT activity from the current study, despite higher mRNA expression. It has been established historically that fasting increased acetaminophen hepatotoxicity in rodents (Walker et al, 1982). It is well known that induction of acetaminophen toxicity in rodents has a circadian component and the timing of acetaminophen dosing is critical for the level of hepatotoxicity that manifests (Schnell et al, 1984).…”

Hepatotoxicity of microcystin-LR in fed and fasted rats

“…In the case of acetaminophen, the mechanism of enhanced toxicity appears to be an increase in a toxic metabolite, resulting from a drop in hepatic glutathione pools (WALKER et al, 1982). A similar explanation for MCYST-LR's toxicity was not supported by a study showing that depressed glutathione levels enhanced mean survival time of mice (DAHLEM et al, 1989).…”

Impaired mitochondrial oxidative energy metabolism following paracetamol‐induced hepatotoxicity in the rat

“…The average weights of the animals in the control and the experimental groups were matched within 5g at the start of the experiment. The animals were fasted overnight and were given paracetamol injections next morning (Walker et al, 1982). Saturated solutions of paracetamol (35 mg ml-') were prepared in warm (45-50'C) saline (0.9% w/v) and animals were injected intraperitoneally (i.p.)…”