Inhibition and activation of acetaminophen reactive metabolite formation by caffeine. Roles of cytochromes P-450IA1 and IIIA2

CA Lee, KE Thummel, TF Kalhorn, SD Nelson and JT Slattery

Department of Pharmaceutics, University of Washington, Seattle 98195.

Caffeine has previously been shown to diminish or potentiate acetaminophen (APAP) hepatotoxicity in rats, depending on induction state. To elucidate the P-450 forms involved in these divergent effects, rat liver microsomes, prepared after pretreatment with various inducers, were used to examine the effect of caffeine on N-acetyl-p- benzoquinone imine (NAPQI) formation. The addition of caffeine to incubations with 3-methylcholanthrene (MC)-induced microsomes resulted in a biphasic effect on the formation of NAPQI. A 43% decrease in NAPQI formation was observed as caffeine concentration was increased from 0 to 0.5 mM; however, NAPQI formation was accelerated as caffeine concentration increased, exceeding the control (no caffeine) value, at caffeine concentrations greater than 2.5 mM. Incubations with purified P-450IA1 showed that as caffeine concentration increased from 0 to 5 mM, a 50% inhibition was observed with no evidence of acceleration. In contrast to MC microsomes, the addition of caffeine to incubations with uninduced and phenobarbital-induced adult rat microsomes resulted in a marked (3- to 4-fold) acceleration of NAPQI formation with no evidence of inhibition. Caffeine (5 mM) also accelerated NAPQI formation in microsomes isolated from diabetic rats, but to a substantially lesser extent (120%), suggesting a modest (if any) effect on P-450IIE1, a form previously shown to form NAPQI from APAP. Interestingly, caffeine caused a 3- to 4-fold increase in NAPQI formation by juvenile male and female rat microsomes, but no activation was observed with adult female rat microsomes. These results suggested that caffeine activated a member of the cytochrome P-450IIIA subfamily.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 19, Issue 2, pp. 348-353, 03/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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