Anomalous susceptibility of the fasted hamster to acetaminophen hepatotoxicity

Biochemical Pharmacology
M G MillerD J Jollow

Abstract

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 glut...Continue Reading

References

Jul 1, 1984·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·B H LauterburgJ R Mitchell
Jan 1, 1982·Drug Metabolism Reviews·D J JollowC Smith
Jan 1, 1958·Proceedings of the Society for Experimental Biology and Medicine·L V BECKB DUNCAN

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Citations

Oct 20, 1992·Biochemical Pharmacology·S C Langley, F J Kelly
Jan 1, 2014·European Journal of Pediatrics·Pierluigi MarzuilloEgidio Barbi
Sep 1, 1987·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·W M LeeR M Galbraith
Feb 15, 1987·Biochemical Pharmacology·V F PriceD J Jollow

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