Tirmenstein M A, Nelson S D
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
J Biol Chem. 1990 Feb 25;265(6):3059-65.
The administration of a hepatotoxic dose of acetaminophen (250 mg/kg) to mice induced the loss of protein thiols in mouse liver. Our data suggest that a significant portion of this loss was due to protein thiol oxidation. The administration of the nonhepatotoxic regioisomer, 3'-hydroxyacetanilide (600 mg/kg) did not produce a similar decrease in liver protein thiols despite producing similar levels of covalent binding. Mice treated with acetaminophen exhibited decreased glutathione peroxidase activity, decreased thioltransferase activity, and decreased adenine nucleotide concentrations in the liver. The increase in urinary allantoin after the administration of acetaminophen suggests that the decrease in adenine nucleotides was due to their degradation in the liver. Acetaminophen also promoted the conversion of the enzyme xanthine dehydrogenase to the oxidase form, and pretreatment of mice with allopurinol, an inhibitor of xanthine oxidase, significantly decreased acetaminophen-mediated hepatotoxicity. The conversion of xanthine dehydrogenase to the oxidase form may lead to a transient increase in the production of activated oxygen species. The increase in activated oxygen species coupled with decreases in glutathione peroxidase and thioltransferase activity may be responsible in part for the increased levels of oxidized protein thiols observed following acetaminophen administration.
给小鼠施用肝毒性剂量的对乙酰氨基酚（250毫克/千克）会导致小鼠肝脏中蛋白质硫醇的损失。我们的数据表明，这种损失的很大一部分是由于蛋白质硫醇氧化。施用非肝毒性区域异构体3'-羟基乙酰苯胺（600毫克/千克）尽管产生了相似水平的共价结合，但并未使肝脏蛋白质硫醇产生类似的减少。用对乙酰氨基酚处理的小鼠肝脏中的谷胱甘肽过氧化物酶活性降低、硫醇转移酶活性降低且腺嘌呤核苷酸浓度降低。施用对乙酰氨基酚后尿中尿囊素增加表明腺嘌呤核苷酸的减少是由于它们在肝脏中的降解。对乙酰氨基酚还促进了黄嘌呤脱氢酶向氧化酶形式的转化，用黄嘌呤氧化酶抑制剂别嘌呤醇对小鼠进行预处理可显著降低对乙酰氨基酚介导的肝毒性。黄嘌呤脱氢酶向氧化酶形式的转化可能导致活性氧生成的短暂增加。活性氧的增加以及谷胱甘肽过氧化物酶和硫醇转移酶活性的降低可能部分导致了对乙酰氨基酚给药后观察到的氧化蛋白质硫醇水平的升高。
