Biochemical changes associated with the potentiation of acetaminophen hepatotoxicity by brief anesthesia with diethyl ether.
Acetaminophen hepatotoxicity in male CD-1 mice was enhanced markedly by brief anesthesia with diethyl ether (ether), and particularly so if acetaminophen was given several hours after ether. The present study was conducted to examine the possible biochemical mechanisms behind this delayed toxicologic synergism. In vitro biochemical studies indicated that ether anesthesia produced a delayed reduction in the activities of glucuronyl transferase and glutathione (GSH) S-transferase, and in the hepatic content of GSH. The hepatic content but not activity of the cytochromes P-450 was initially reduced by ether but recovered by the time of maximal toxicologic enhancement. In vivo studies showed that ether produced a small decrease in the plasma concentrations of glucuronide and sulfate conjugates of acetaminophen, with a concomitant, minor increase in the half-life of acetaminophen, and a major increase in the bioactivation of acetaminophen, as determined by an early, 2-fold increase in the plasma GSH and cysteine conjugates of acetaminophen, and a 3-fold increase in the covalent binding of acetaminophen to hepatocellular protein. Decreases produced by ether in the in vivo production of acetaminophen glucuronide correlated with increasing plasma concentrations of unmetabolised acetaminophen, decreasing hepatic GSH content and increasing covalent binding of acetaminophen to hepatocellular protein when these measurements were performed in the same animals. The biochemical mechanisms underlying the potentiation of acetaminophen hepatoxicity as measured by plasma glutamic pyruvic transaminase concentrations appeared to be due to delayed, complex effects of ether upon multiple enzymatic pathways of acetaminophen elimination and detoxification.
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000758:Anesthesia / Q000009:adverse effects*; D000818:Animals; D004357:Drug Synergism; D004986:Ether / Q000633:toxicity*; D005019:Ethyl Ethers / Q000633:toxicity*; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D005982:Glutathione Transferase / Q000032:analysis; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D005019:Ethyl Ethers; D005965:Glucuronates; D004986:Ether; D000082:Acetaminophen; D005982:Glutathione Transferase; D000410:Alanine Transaminase; D005978:Glutathione