RT Journal Article
SR Electronic
T1 Inhibition and activation of acetaminophen reactive metabolite formation by caffeine. Roles of cytochromes P-450IA1 and IIIA2.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 348
OP 353
VO 19
IS 2
A1 C A Lee
A1 K E Thummel
A1 T F Kalhorn
A1 S D Nelson
A1 J T Slattery
YR 1991
UL http://dmd.aspetjournals.org/content/19/2/348.abstract
AB 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)