Effect of diethyl ether on the bioactivation, detoxification, and hepatotoxicity of acetaminophen in vitro and in vivo.
Our working hypothesis for designing this study involved early inhibition by ether of P-450-dependent bioactivation and glucuronyl transferase-dependent "detoxification", with an earlier recovery of bioactivation. The combined in vivo and in vitro results from the same animals indicate that the increased susceptibility to acetaminophen hepatotoxicity may have been due to a combination of delayed decreases induced by ether in the activities of glucuronyl transferase, sulfotransferase and GSH S-transferase, along with a depletion of hepatic GSH. The small decrease in hepatic content of cytochromes P-450 at 2 hr when toxicologic enhancement was minimal, together with repletion at 8 hr when enhancement was maximal, while the above detoxification pathways were inhibited, is compatible with our hypothesis. However, the lack of an accompanying change in the activity of P-450 suggests either that a different P-450 isoenzyme is involved, or that P-450 activity was not toxicologically limiting. The toxicological imbalance in the bioactivation and detoxification of acetaminophen observed after ether pretreatment was evidenced by significant increases both in the plasma concentrations of GSH and cysteine conjugates, and in the covalent binding of acetaminophen to hepatocellular protein.
D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001711:Biotransformation; D003545:Cysteine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D004986:Ether / Q000494:pharmacology*; D005019:Ethyl Ethers / Q000494:pharmacology*; D005965:Glucuronates / Q000097:blood; D005978:Glutathione / Q000097:blood; D008658:Inactivation, Metabolic; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D013431:Sulfates / Q000097:blood
D005019:Ethyl Ethers; D005965:Glucuronates; D013431:Sulfates; D004986:Ether; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine