Wells P G, Ramji P, Ku M S
Fundam Appl Toxicol. 1986 Feb;6(2):299-306. doi: 10.1016/0272-0590(86)90244-7.
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)
对乙酰氨基酚（泰诺林）是一种广泛使用的镇痛/解热药物，它通过细胞色素P - 450酶促生物活化或产生毒性，形成具有肝毒性的反应性中间代谢产物。已表明，用乙醚进行短暂全身麻醉可抑制产生毒性的细胞色素P - 450和酶促葡萄糖醛酸化，后者在通过无毒性途径消除的对乙酰氨基酚中占比高达60%。因此，如果平衡有利于生物活化，乙醚可能会对生物活化和“解毒”途径产生时间上有差异的抑制作用，从而增强对乙酰氨基酚的肝毒性。为评估这种可能性，将雄性NIH品系小鼠分成不同组，在乙醚麻醉5分钟后的不同时间给予对乙酰氨基酚。根据血浆谷丙转氨酶（GPT）浓度测定，乙醚使对乙酰氨基酚的肝毒性增强了40倍。仅当对乙酰氨基酚给药延迟时才观察到这种毒理学增强现象，在乙醚麻醉后6小时给予对乙酰氨基酚时增强作用最大，延迟16小时则无影响。使用氟烷（氟罗生）作为全身麻醉剂，对雄性CD - 1小鼠进行了类似研究，麻醉时间分别为5分钟或1小时。虽然5分钟的氟烷麻醉没有效果，但麻醉持续1小时会使根据GPT峰值浓度测定的对乙酰氨基酚肝毒性增加10倍，在氟烷对照组中未观察到肝毒性。毒理学增强仅在对乙酰氨基酚延迟给药时出现；然而，延迟6小时观察到的最大增强在延迟12小时时仍然明显。相反，如果在氟烷麻醉后2小时或18小时给予对乙酰氨基酚，则观察到对乙酰氨基酚肝毒性受到抑制。（摘要截取自250字）
