Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane.
Acetaminophen (Tylenol) is a widely used analgesic/antipyretic drug which is enzymatically bioactivated, or toxified, by the cytochromes P-450 to a hepatotoxic reactive intermediary metabolite. Brief general anesthesia with diethyl ether has been shown to inhibit both the toxifying cytochromes P-450 and enzymatic glucuronidation, the latter constituting up to 60% of acetaminophen elimination via a nontoxifying pathway. Thus ether potentially could produce a temporally differentiated inhibition of bioactivating and "detoxifying" pathways, resulting in an enhancement of acetaminophen hepatotoxicity if the balance favored bioactivation. To evaluate this possibility, separate groups of male NIH strain mice were treated with acetaminophen at different times after 5 min of anesthesia with ether. Ether produced a 40-fold enhancement in acetaminophen hepatotoxicity as determined by plasma glutamic-pyruvic transaminase (GPT) concentrations. This toxicologic enhancement was observed only if acetaminophen administration was delayed, with a maximal enhancement when acetaminophen was given 6 hr after ether, and no effect with a delay of 16 hr. Similar studies in male CD-1 mice were carried out using halothane (Fluothane) as the general anesthetic given either over 5 min or over 1 hr. While halothane given over 5 min had no effect, a 1 hr anesthetic duration produced a 10-fold increase in acetaminophen hepatotoxicity as determined by peak GPT concentration, with no observed hepatotoxicity in the halothane controls. Toxicologic enhancement occurred only with delayed administration of acetaminophen; however, the maximal enhancement observed with a 6-hr delay was still evident with a 12-hr delay. Conversely, inhibition of acetaminophen hepatotoxicity was observed if acetaminophen was given either 2 hr or 18 hr after halothane.(ABSTRACT TRUNCATED AT 250 WORDS)
P G
PG
Wells
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P
Ramji
M S
MS
Ku
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000769:Anesthesia, Inhalation; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D004357:Drug Synergism; D004986:Ether / Q000633:toxicity*; D005019:Ethyl Ethers / Q000633:toxicity*; D006221:Halothane / Q000633:toxicity*; D008297:Male; D051379:Mice; D013997:Time Factors
D005019:Ethyl Ethers; D004986:Ether; D000082:Acetaminophen; D006221:Halothane