Effect of Diethyl Ether on the Bioactivation, Detoxification, and Hepatotoxicity of Acetaminophen in Vitro and in Vivo
Diethyl ether (ether) is used widely as a general anesthetic in animal research, and it remains a convenient human anesthetic in some third world countries. Acetaminophen (N-acetyl-p-aminophenol, APAP, Tylenol®) is a widely used analgesic/antipyretic drug which in high doses can cause centrilobular hepatic necrosis in animals (Boyd and Bereczky, 1966) and humans (Proudfoot and Wright, 1970). Hepatotoxicity is thought to result from cytochromes P-450-catalysed bioactivation of a small amount of acetaminophen to a toxic, reactive intermediary metabolite (Mitchell et al., 1973a), while up to 60% of acetaminophen is eliminated by a competing glucuronidation pathway (fig. 1). Under normal conditions, the reactive intermediate is evanescent, being immediately detoxified by enzymatic conjugation with hepatic reduced glutathione (GSH) and subsequently excreted as cysteine and N-acetylcysteine conjugates (Mitchell et al., 1973b). However, if the amount of acetaminophen bioactivated is increased, or if detoxification of the reactive intermediate is reduced, then the available reactive intermediate arylates hepatic macromolecules, which is thought to initiate processes leading to hepatocellular necrosis (Mitchell et al., 1973a; Jollow et al., 1973).
KeywordsGlutathione Cysteine Doxorubicin Aniline Diphenylhydantoin
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