Mechanism of increased hepatotoxicity of acetaminophen by the simultaneous administration of caffeine in the rat.
The simultaneous administration of caffeine has been shown to potentiate acetaminophen-induced hepatotoxicity. In the present study, the mechanisms of this effect were studied. Male Sprague-Dawley rats, fasted for 18 hr, were given acetaminophen (0.5 g/kg) and/or caffeine (0.1 g/kg) i.p. Two hours later, the depletion of hepatic reduced glutathione (GSH) induced by acetaminophen was more pronounced by the concomitant administration of caffeine, although the effect of caffeine alone on the hepatic GSH content was minimal at this dose. Covalent binding of a reactive metabolite of acetaminophen to hepatic proteins was increased by caffeine although the free acetaminophen content in the liver was not affected. In isolated rat hepatocytes prepared from normal animals, caffeine enhanced acetaminophen-induced GSH depletion and potentiated covalent binding of the reactive metabolite to cellular proteins. The extracellular release of GSH + oxidized glutathione was decreased by acetaminophen, and this decrease was potentiated further by the addition of caffeine. In the cells, the production of acetaminophen-GSH conjugate also was increased in the presence of caffeine, whereas that of glucuronide conjugate was decreased. In microsomes, NADPH-dependent production of acetaminophen-GSH conjugate was increased in the presence of caffeine. Thus, caffeine appears to potentiate acetaminophen-induced hepatotoxicity mainly by enhancing the production of a reactive metabolite of acetaminophen by mixed function oxidases. To what extend caffeine-induced GSH depletion plays a role is to be clarified.
Sato
C
C
The Second Department of Internal Medicine, School of Medicine, Tokyo Medical and Dental University, Japan.
Izumi
N
N
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D005978:Glutathione / Q000032:analysis; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D002110:Caffeine; D005978:Glutathione; C034780:3-(glutathion-S-yl)acetaminophen