Price V F, Jollow D J
Department of Pharmacology, Medical University of South Carolina, Charleston 29425.
Toxicol Appl Pharmacol. 1989 Nov;101(2):356-69. doi: 10.1016/0041-008x(89)90283-4.
Cysteine is required for the synthesis of cosubstrates for two pathways of acetaminophen metabolism: 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for sulfation and glutathione (GSH) for detoxification of the reactive metabolite (N-acetyl-p-benzoquinoneimine, NAPQI). Dietary deficiency of cysteine may reduce hepatic production of PAPS and GSH and thereby reduce metabolism of the drug (by sulfation and detoxification of NAPQI) and hence lead to potentiation of acetaminophen liver injury. Conversely, limitation of sulfur-containing amino acids could result in depression of protein synthesis and hepatic cytochrome P450 levels, and hence in decreased reactive metabolite formation and decreased liver injury. To determine whether the potentiating effects exceed the protective effects, rats were fed isocaloric AIN-76 liquid diets containing various levels of methionine as the sole source of sulfur in the diet for 3 weeks prior to administration of acetaminophen. Sulfur deficiency was assessed by measuring urinary inorganic sulfate levels. Sulfur-deficient diets retarded growth but did not affect nitrogen balance. Sulfur-deficient animals had lower basal levels of hepatic GSH. Pharmacokinetic studies revealed that at low doses of acetaminophen (20 mg/kg), animals fed sulfur-deficient diets metabolized the drug more slowly due to a markedly reduced sulfation capacity, whereas at the high dose of acetaminophen (400 mg/kg), rats that were fed sulfur-deficient diets had a higher clearance of the drug than rats that were fed the complete diet. The increase in clearance was due largely to an enhanced glucuronidation capacity and an enhanced P450-dependent oxidation as indicated by mercapturate formation. Histologic studies revealed that rats fed sulfur-deficient diets showed increases in both incidence and severity of acetaminophen hepatic necrosis. Thus, the potentiating effects exceeded the protective effects. These observations raise the possibility that nutritional inadequacy of sulfur-containing amino acids which could occur during protein malnutrition may similarly enhance susceptibility to acetaminophen liver injury in humans.
用于硫酸化的3'-磷酸腺苷-5'-磷酸硫酸酯（PAPS）和用于活性代谢物（N-乙酰-p-苯醌亚胺，NAPQI）解毒的谷胱甘肽（GSH）。饮食中半胱氨酸缺乏可能会降低肝脏中PAPS和GSH的生成，从而减少药物的代谢（通过NAPQI的硫酸化和解毒），进而导致对乙酰氨基酚肝损伤的增强。相反，含硫氨基酸的限制可能会导致蛋白质合成和肝细胞色素P450水平降低，从而导致活性代谢物形成减少和肝损伤减轻。为了确定增强作用是否超过保护作用，在给予对乙酰氨基酚之前3周，给大鼠喂食等热量的AIN-76液体饮食，其中含有不同水平的蛋氨酸作为饮食中硫的唯一来源。通过测量尿无机硫酸盐水平评估硫缺乏情况。缺硫饮食会阻碍生长，但不影响氮平衡。缺硫动物的肝脏GSH基础水平较低。药代动力学研究表明，在低剂量对乙酰氨基酚（20 mg/kg）时，喂食缺硫饮食的动物由于硫酸化能力明显降低，药物代谢较慢，而在高剂量对乙酰氨基酚（400 mg/kg）时，喂食缺硫饮食的大鼠比喂食完整饮食的大鼠对药物的清除率更高。清除率的增加主要是由于葡萄糖醛酸化能力增强和如巯基尿酸形成所示的P450依赖性氧化增强。组织学研究表明，喂食缺硫饮食的大鼠对乙酰氨基酚肝坏死的发生率和严重程度均增加。因此，增强作用超过了保护作用。这些观察结果提出了一种可能性，即在蛋白质营养不良期间可能发生的含硫氨基酸营养不足可能同样会增强人类对对乙酰氨基酚肝损伤的易感性。
