Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites.
Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites.
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发表时间：
1988
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通讯作者：
Z. Gregus;C. Madhu;C. Klaassen
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作者：
Z. Gregus;C. Madhu;C. Klaassen
对乙酰氨基酚(AA)被转化为一种有毒的电泳体，随后可能形成谷胱甘肽结合物(AA-GS)。除了由AA-GS及其水解产物(AA-半胱氨酸甘氨酸、AA-半胱氨酸和AA-硫代尿酸)组成的毒性代谢产物外，还形成了解毒途径的代谢产物，如AA-葡萄糖醛酸苷和AA-硫酸盐。为了评价这些相互对立的途径在AA诱导的肝损伤易感性物种变异中的作用，分别对易受AA诱导的肝损伤的仓鼠和小鼠，以及对AA诱导的肝损伤相对抵抗的大鼠、兔和豚鼠给予AA，并在给药后2小时同时测定胆汁和尿中AA代谢产物的排泄量。AA敏感物种排泄27%~42%的剂量作为毒害途径代谢物，而抗性物种仅排泄5%~7%的剂量作为毒害途径代谢物。大多数中毒途径的代谢物存在于胆汁中，其组成反映了肝脏的γ-谷氨酰转肽酶活性；仓鼠和小鼠(低γ-谷氨酰转肽酶活性)主要排泄AA-GS，而兔和豚鼠的胆汁(高γ-谷氨酰转肽酶活性)含有大量的AA-GS水解物。因此，胆汁中AA-GS及其水解物的排泄量可作为AA毒性激活的一个指标。解毒途径代谢产物(AA-葡萄糖醛酸苷和AA-硫酸盐)在豚鼠、大鼠、小鼠、兔和仓鼠体内的排泄量分别为剂量的74%、62%、41%、27%和12%。
Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic gamma-glutamyltranspeptidase activity; hamsters and mice (low gamma-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high gamma-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively.(ABSTRACT TRUNCATED AT 250 WORDS)