Abstract
A circadian rhythm in the toxicity of acetaminophen administered at different times of the day was exhibited in male mice. Peak lethality (70% dead) occurred at 1800 hr and nadir lethality (10% dead) occurred at 1000 hr. Hepatic nonprotein sulfhydryl (NPS) concentrations also varied in a circadian manner and were found to exhibit an inverse relationship to the acetaminophen lethality rhythm, with the highest hepatic concentrations occurring at 1000 hr and the lowest concentrations occurring at 1800 hr. At 1800 hr when acetaminophen lethality was greatest and NPS levels the lowest, more reactive acetaminophen metabolites were found covalently bound to hepatic macromolecules as compared to those bound at 1000 hr when NPS levels were highest and acetaminophen lethality was lowest. Hepatic cytochrome P-450 levels measured at these two daily time periods did not differ. The plasma half-life of acetaminophen was significantly decreased at the 1000 hr time period as compared to the 1800 hr time period. These findings suggest that the normal daily changes in NPS levels may influence the lethality of acetaminophen.
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