JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kalhorn, T. F.
Right arrow Articles by Nelson, S. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kalhorn, T. F.
Right arrow Articles by Nelson, S. D.

Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states

TF Kalhorn, CA Lee, JT Slattery and SD Nelson

Department of Pharmaceutics, University of Washington, Seattle.

The effect of caffeine, theophylline and theobromine on acetaminophen- induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3- methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene- induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.

Volume 252, Issue 1, pp. 112-116, 01/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
K. K. Wolf, S. G. Wood, J. A. Hunt, B. W. Walton-Strong, K. Yasuda, L. Lan, S. X. Duan, Q. Hao, S. A. Wrighton, E. H. Jeffery, et al.
ROLE OF THE NUCLEAR RECEPTOR PREGNANE X RECEPTOR IN ACETAMINOPHEN HEPATOTOXICITY
Drug Metab. Dispos., December 1, 2005; 33(12): 1827 - 1836.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
C. A. Lee, P. T. Manyike, K. E. Thummel, S. D. Nelson, and J. T. Slattery
Mechanism of Cytochrome P450 Activation by Caffeine and 7,8-Benzoflavone in Rat Liver Microsomes
Drug Metab. Dispos., October 1, 1997; 25(10): 1150 - 1156.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics.