Jørgensen L, Thomsen P, Poulsen H E
Department of Medicine A, Rigshospitalet, University of Copenhagen, Denmark.
Pharmacol Toxicol. 1988 May;62(5):267-71. doi: 10.1111/j.1600-0773.1988.tb01885.x.
Hepatic necrosis due to an oral acetaminophen overdose (4.25 g/kg b.wt.) was prevented by pretreatment with disulfiram 100 mg/kg, given for 3 weeks or as a single dose. Twenty-four hours after acetaminophen the impairment of hepatic function, measured as prothrombin index, and the depletion of hepatic glutathione were prevented. Hepatic cytochrome P-450 levels were unchanged but cytochrome P-450 mediated p-nitroanisole demethylation was reduced by disulfiram pretreatment. Disulfiram pretreatment reduced 24 hour urinary excretion of acetaminophen-mercapturate and- cysteine while excretion of -sulfate and -glucuronide was unchanged. After 72 hours acetaminophen induced hepatic necrosis were prevented. Identical observations were made in animals pretreated with disulfiram for 3 weeks. Five hours after acetaminophen overdose its irreversible binding to hepatic proteins was not changed. After 24 hours, however, it was increased in animals pretreated with a single disulfiram dose and unchanged in animals pretreated for 3 weeks. The protective mechanism of disulfiram after acetaminophen overdose is not mediated via a change in overall irreversible binding of acetaminophen to hepatic protein.
给予100mg/kg双硫仑预处理3周或单次给药，可预防口服对乙酰氨基酚过量（4.25g/kg体重）所致的肝坏死。对乙酰氨基酚给药24小时后，以凝血酶原指数衡量的肝功能损害及肝谷胱甘肽耗竭得到预防。肝微粒体细胞色素P-450水平未变，但双硫仑预处理使细胞色素P-450介导的对硝基苯甲醚去甲基化降低。双硫仑预处理使对乙酰氨基酚半胱氨酸结合物和半胱氨酸的24小时尿排泄减少，而硫酸盐和葡萄糖醛酸结合物的排泄未变。72小时后，对乙酰氨基酚诱导的肝坏死得到预防。对用双硫仑预处理3周的动物也观察到相同结果。对乙酰氨基酚过量5小时后，其与肝蛋白的不可逆结合未变。然而，24小时后，单次给予双硫仑预处理的动物中其结合增加，而预处理3周的动物中其结合未变。对乙酰氨基酚过量后双硫仑的保护机制并非通过改变对乙酰氨基酚与肝蛋白的总体不可逆结合来介导。
