Anomalous susceptibility of the fasted hamster to acetaminophen hepatotoxicity.
The effect of an acute fast on susceptibility to acetaminophen-induced hepatotoxicity was investigated in male Golden Syrian hamsters. Overnight starvation markedly elevated hepatic levels of glutathione throughout the diurnal cycle (peak concentration: 10.6 +/- 0.06 mM vs 7.3 +/- 0.3mM in controls). However, despite this apparent increase in the glutathione protective capacity of the liver, acetaminophen-induced hepatic necrosis was modestly potentiated by fasting, as judged by liver histology and elevation of serum transaminase (SGOT) activity. Parallel pharmacokinetic studies indicated that the overall elimination rate constant for acetaminophen was decreased in fasted animals, due largely to decreases in the apparent rate constants for formation of acetaminophen glucuronide and acetaminophen mercapturate. Formation of acetaminophen sulfate was not affected by fasting. Since the major nontoxic pathway (glucuronide) and the toxic pathway (as measured by mercapturate) decreased to a similar extent, the data indicate that the anomalous lack of protection cannot be explained on the basis of altered metabolic disposition of the drug. Measurement of hepatic glutathione levels revealed that, despite the higher initial level of glutathione in the fasted animals, the nadir to which liver glutathione levels fell after acetaminophen was the same in fed and fasted animals. Comparison of the amount of acetaminophen mercapturate in the urine with the amount of glutathione which disappeared from the liver showed close agreement for fed animals, but a major discrepancy for fasted hamsters. These data indicate that a major fraction of glutathione in the liver of the fasted hamsters is not utilized for detoxification of the acetaminophen reactive metabolite and hence does not contribute to the glutathione protective capacity.
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D006224:Cricetinae; D005215:Fasting; D005978:Glutathione / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D013997:Time Factors
D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D005978:Glutathione; C048094:acetaminophen mercapturate