Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen.
The effect of 5 mM ethanol, maintained by a constant infusion, on the hepatotoxicity and disposition of acetaminophen was examined in 3-methylcholanthrene-induced rats. Ethanol infusion, which began 1 hr before acetaminophen and was maintained for 9 hr, resulted in a 2.8-fold higher hepatic glutathione concentration 6 hr after acetaminophen than did saline infusion. Ethanol infusion also diminished the rise in the 24 hr postacetaminophen plasma alanine transferase concentration by approximately 46%. Ethanol (5 mM) had only a modest effect on the oxidation of acetaminophen in rat liver microsomes, 7 to 14% inhibition over a range of acetaminophen concentration of 0.1 to 3 mM, whereas a 30 to 40% decline of covalent binding of acetaminophen-derived material was observed in vivo (peak acetaminophen concentration approximately 3 mM). Thus, a mechanism other than direct inhibition of cytochrome(s) P-450 by ethanol is invoked to account for the protective effect of ethanol. Ethanol infusion increased the ratio of total hepatocellular NADH/NAD+, and the ratio of free NADH/NAD+ in cytosol and mitochondria as a consequence of sequential oxidations of ethanol producing acetaldehyde and acetic acid in the respective compartments. The toxic electrophile produced by cytochrome P-450 oxidation of acetaminophen, N-acetyl-p-benzoquinoneimine, is reduced rapidly by NADH in aqueous solution. However, acetaminophen alone also increased free NADH/NAD+ in cytosol, and there was no indication that N-acetyl-p-benzoquinoneimine consumed NADH generated by the oxidation of ethanol. Ethanol infusion also increased the ratio of total hepatocellular NADPH/NADP+, apparently through transhydrogenation of NADP+ by NADH in mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
Thummel
K E
KE
Department of Pharmaceutics, University of Washington, Seattle.
Slattery
J T
JT
Nelson
S D
SD
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D009243:NAD; D000082:Acetaminophen; D000431:Ethanol; D009249:NADP; D005978:Glutathione