Kwan D, Bartle W R, Walker S E
Department of Pharmacy, Queen Elizabeth Hospital, Toronto, Ontario, Canada.
Dig Dis Sci. 1995 Sep;40(9):1951-5. doi: 10.1007/BF02208663.
J.M., a healthy, 25-year-old male, volunteered for a study involving warfarin and acetaminophen. Acetaminophen 1 g four times a day was started for 21 days. Liver function tests taken at regular intervals for the first 12 days were unremarkable. On day 18, however, aspartate aminotransferase (AST) was 527 IU/liter and alanine aminotransferase (ALT) was 166 IU/liter. Acetaminophen was discontinued and serum transaminase levels returned to baseline levels two weeks later (AST = 26, ALT = 20). Analysis of J.M.'s urine samples over the first 18 days showed excretion patterns of glucuronide, sulfate, and glutathione derived cysteine and mercapturic acid conjugates were similar to the other subjects in the study. Acetaminophen causes hepatotoxicity in overdose or malnourished or alcoholic patients, none of which applied to our subject. Differences in metabolic activation and capacity for glutathione synthesis can predispose individuals given therapeutic doses of acetaminophen to adverse effects. Failure to detoxify a highly reactive metabolite, formed by P-450 metabolism, via glutathione conjugation is responsible for the development of acute hepatic necrosis. Accumulation of the toxic metabolite due to depleted glutathione stores may have occurred with prolonged high dosing in our subject and been responsible for his abnormal rise in liver enzymes.
J.M.是一名25岁的健康男性，他自愿参与一项涉及华法林和对乙酰氨基酚的研究。开始每天服用4次1克对乙酰氨基酚，持续21天。在开始的12天里定期进行的肝功能测试结果均无异常。然而，在第18天，天冬氨酸转氨酶（AST）为527国际单位/升，丙氨酸转氨酶（ALT）为166国际单位/升。停用对乙酰氨基酚，两周后血清转氨酶水平恢复到基线水平（AST = 26，ALT = 20）。对J.M.头18天的尿液样本分析显示，葡萄糖醛酸、硫酸盐以及谷胱甘肽衍生的半胱氨酸和硫醚氨酸结合物的排泄模式与该研究中的其他受试者相似。对乙酰氨基酚在过量用药、营养不良或酗酒的患者中会导致肝毒性，但这些情况在我们的受试者身上均未出现。代谢激活和谷胱甘肽合成能力的差异可能使接受治疗剂量对乙酰氨基酚的个体易产生不良反应。通过谷胱甘肽结合作用未能将由P - 450代谢形成的高反应性代谢物解毒，是急性肝坏死发生的原因。在我们的受试者中，由于长期高剂量用药可能发生了谷胱甘肽储备耗尽导致的有毒代谢物蓄积，并导致了他肝酶的异常升高。
