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Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states.
J Pharmacol Exp Ther. 1990 Jan; 252(1):112-6.JP

Abstract

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.

Authors+Show Affiliations

Kalhorn TF
Department of Pharmaceutics, University of Washington, Seattle.
Lee CA
No affiliation info available
Slattery JT
No affiliation info available
Nelson SD
No affiliation info available

MeSH

AcetaminophenAlanine TransaminaseAnimalsBenzoquinonesBody TemperatureCaffeineGlutathioneIminesLiverMaleMethylcholanthrenePhenobarbitalRatsRats, Inbred StrainsTheobromineTheophylline

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2299585

Citation

Kalhorn, T F., et al. "Effect of Methylxanthines On Acetaminophen Hepatotoxicity in Various Induction States." The Journal of Pharmacology and Experimental Therapeutics, vol. 252, no. 1, 1990, pp. 112-6.
Kalhorn TF, Lee CA, Slattery JT, et al. Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states. J Pharmacol Exp Ther. 1990;252(1):112-6.
Kalhorn, T. F., Lee, C. A., Slattery, J. T., & Nelson, S. D. (1990). Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states. The Journal of Pharmacology and Experimental Therapeutics, 252(1), 112-6.
Kalhorn TF, et al. Effect of Methylxanthines On Acetaminophen Hepatotoxicity in Various Induction States. J Pharmacol Exp Ther. 1990;252(1):112-6. PubMed PMID: 2299585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states. AU - Kalhorn,T F, AU - Lee,C A, AU - Slattery,J T, AU - Nelson,S D, PY - 1990/1/1/pubmed PY - 1990/1/1/medline PY - 1990/1/1/entrez SP - 112 EP - 6 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 252 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/2299585/Effect_of_methylxanthines_on_acetaminophen_hepatotoxicity_in_various_induction_states_ DB - PRIME DP - Unbound Medicine ER -