Interaction of caffeine with acetaminophen in mice: schedule dependency of the antagonism by caffeine of acetaminophen hepatotoxicity and the effects of caffeine metabolites, allopurinol, and diethyl ether.
Administration of caffeine (CAF) to mice as early as 6 hr prior to injection of a hepatotoxic but nonlethal dose of acetaminophen (ACM) significantly antagonized the hepatotoxic action of ACM as judged by serum levels of alanine aminotransferase (ALT) activity. Administration of CAF after ACM produced complete antagonism only when CAF was given no later than 1 hr after ACM. Administration of CAF daily for 3 days prior to injection of ACM enhanced ACM toxicity markedly, but little or no toxicity ensued when CAF-pretreated mice received ACM followed immediately by CAF. The four primary metabolites of CAF, 1,3-dimethylxanthine (theophylline), 3,7-dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), and 1,3,7-trimethyluric acid were effective and virtually complete antagonists of ACM-induced hepatotoxicity when given immediately after ACM, as were the secondary metabolites, 1-methylxanthine and 1,3-dimethyluric acid. Allopurinol, which reduces theophylline clearance, increases the rate of oxidative N-demethylation of theophylline to 1-methylxanthine, and inhibits conversion of 1-methylxanthine to 1-methyluric acid, was also a dose-dependent antagonist of ACM-induced hepatotoxicity. The hepatotoxic response of mice to ACM is exaggerated by a brief period of diethyl ether anesthesia; CAF given immediately after ACM to previously anesthetized mice suppressed this response and maintained serum ALT levels at control values. It is suggested that CAF and its primary metabolites compete with ACM for biotransformation by the cytochrome P-450 mixed function oxidase system, thereby reducing the rate of formation of the hepatotoxic ACM metabolite.
Gale
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GR
Veterans Administration Medical Center, Charleston, SC 29403.
Smith
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D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D004986:Ether / Q000494:pharmacology*; D005019:Ethyl Ethers / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA
D005019:Ethyl Ethers; D004986:Ether; D000082:Acetaminophen; D002110:Caffeine; D000431:Ethanol; D000493:Allopurinol; D000410:Alanine Transaminase