title: Effect of caffeine on acetaminophen hepatotoxicity in cultured hepatocytes treated with ethanol and isopentanol.
abstract: Pretreatment of cultured rat hepatocytes with ethanol alone or in combination with isopentanol, the major higher chain alcohol in alcoholic beverages, significantly increased CYP3A and acetaminophen (APAP) bioactivation, with no increase in APAP toxicity. Caffeine has previously been shown to activate CYP3A activity in vitro and to increase APAP hepatotoxicity in rodents pretreated with prototypic inducers of CYP3A. Here we found that caffeine enhanced APAP toxicity in cultured rat hepatocytes pretreated with the alcohols. The caffeine-mediated increase in APAP toxicity was similar in cells treated with ethanol or isopentanol alone or in combination. These findings suggest that even small increases in CYP3A are sufficient to support caffeine-enhanced APAP toxicity. Triacetyloleandomycin inhibited CYP3A activity in intact hepatocytes and protected alcohol-pretreated cells from caffeine enhancement of APAP toxicity. This protection was associated with decreased formation of the toxic metabolite of APAP. The results indicate that CYP3A is responsible for the caffeine-mediated stimulation of APAP toxicity. Our results suggest that caffeine may be an additional risk factor for developing alcohol-mediated APAP hepatotoxicity.
authors.affiliation: Department of Pharmacology/Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03756, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: DiPetrillo
authors.forename: Sheryl
authors.initials: S
authors.lastname: Wood
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Kostrubsky
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chatfield
authors.forename: Jenna
authors.initials: J
authors.lastname: Bement
authors.forename: Steven
authors.initials: S
authors.lastname: Wrighton
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jeffery
authors.forename: Peter
authors.initials: P
authors.lastname: Sinclair
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sinclair
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D000439:Pentanols / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D000439:Pentanols; D000082:Acetaminophen; D002110:Caffeine; D000431:Ethanol; D014217:Troleandomycin; C029683:isopentyl alcohol; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating