ENHANCED ACETAMINOPHEN TOXICITY IN RATS WITH BILIRUBIN GLUCURONYL TRANSFERASE DEFICIENCY
ENHANCED ACETAMINOPHEN TOXICITY IN RATS WITH BILIRUBIN GLUCURONYL TRANSFERASE DEFICIENCY
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DOI：
10.1002/hep.1840100207
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发表时间：
1989-08-01
期刊：
影响因子：
13.5
通讯作者：
WELLS, PG
中科院分区：
文献类型：
--
作者：
DEMORAIS, SMF;WELLS, PG
葡萄糖醛酸化是消除对乙酰氨基酚的主要途径，使其从细胞色素P-450催化的脱水途径转移。如果同时缺乏其他葡萄糖醛酸基转移酶同工酶，则胆红素UDP-葡萄糖醛酸基转移酶的遗传缺陷可能使人类和动物易受广泛葡萄糖醛酸化药物毒性的影响。纯合子和杂合子古恩大鼠分别严重和中度缺乏葡萄糖醛酸基转移酶。对纯合子和杂合子古恩大鼠和Wistar对照大鼠腹腔注射对乙酰氨基酚（500 mg/kg）。分别通过ALT和血尿素氮的血浆峰浓度评估肝和肾细胞损伤。与Wistar对照组相比，纯合子和杂合子古恩大鼠的ALT浓度分别高出115倍和9倍。血尿素氮仅在纯合子古恩大鼠中升高（3倍）。高效液相色谱法测定了对乙酰氨基酚的生物转化。与Wistar对照组相比，纯合子和杂合子古恩大鼠的对乙酰氨基酚葡萄糖醛酸化分别降低了72%和35%（p< 0.05）。对乙酰氨基酚葡萄糖醛酸苷的产生与ALT浓度呈负相关（r=-0.89，p< 0.001）。谷胱甘肽衍生代谢物的产生反映了对乙酰氨基酚的生物活化作用，在古恩大鼠中高出2至3倍（p< 0.05），并与ALT浓度相关（r= 0.90，p< 0.001）。
Glucuronidation is the major pathway for elimination of acetaminophen, diverting it from the toxifying pathway catalyzed by cytochromes P-450. A genetic deficiency in bilirubin UDP-glucuronyl transferase may predispose humans and animals to the toxicity of drugs that are extensively glucuronidated, if other glucuronyl transferase isoenzymes are concurrently deficient. Homozygous and heterozygous Gunn rats are, respectively, severely and moderately deficient in glucuronyl transferase. Acetaminophen (500 mg per kg) was administered intraperitoneally to homozygous and heterozygous Gunn rats and to Wistar controls. Hepatic and renal cellular damage was assessed by peak plasma concentrations of ALT and blood urea nitrogen, respectively. Homozygous and heterozygous Gunn rats showed, respectively, 115-fold and 9-fold higher ALT concentrations compared to Wistar controls. Blood urea nitrogen was elevated only in the homozygous Gunn rats (3-fold). Biotransformation of acetaminophen was measured by high-performance liquid chromatography. Acetaminophen glucuronidation was decreased by 72 and 35%(p< 0.05), respectively, in the homozygous and heterozygous Gunn rats compared with Wistar controls. Production of acetaminophen glucuronide correlated negatively with ALT concentration (r=− 0.89, p< 0.001). Production of glutathione-derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3-fold higher in the Gunn rats (p< 0.05) and correlated with ALT concentrations (r= 0.90, p< 0.001).