title: Interaction of caffeine with acetaminophen. 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents.
abstract: The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.
authors.affiliation: Division of Nutritional Sciences, University of Illinois, Urbana-Champaign 61801.
authors.forename: S
authors.initials: S
authors.lastname: Jaw
authors.forename: E H
authors.initials: EH
authors.lastname: Jeffery
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000096:Acetone; D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones; D016227:Benzoquinones / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003907:Dexamethasone; D004347:Drug Interactions; D004789:Enzyme Activation; D005260:Female; D007097:Imines / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008107:Liver Diseases / Q000201:enzymology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D010634:Phenobarbital; D019324:beta-Naphthoflavone
chemical_list: D001571:Benzoflavones; D016227:Benzoquinones; D007097:Imines; D007527:Isoenzymes; D000096:Acetone; D000082:Acetaminophen; D002110:Caffeine; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000633:Aminopyrine N-Demethylase; C028473:N-acetyl-4-benzoquinoneimine; D010634:Phenobarbital