Tirmenstein M A, Nelson S D
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
J Biol Chem. 1989 Jun 15;264(17):9814-9.
Acetaminophen (250 mg/kg) administered intraperitoneally to fasted, phenobarbital-induced mice produced hepatotoxicity. No hepatotoxicity was observed after the administration of the regioisomer 3'-hydroxyacetanilide (600 mg/kg). Similar levels of covalent binding to liver homogenates occurred in mice receiving either acetaminophen or 3'-hydroxyacetanilide at these doses. However, subcellular fractionation techniques revealed that the acetaminophen treatment produced greater levels of covalent binding to mitochondrial proteins than 3'-hydroxyacetanilide. In addition, acetaminophen depleted mitochondrial glutathione levels more extensively than 3'-hydroxyacetanilide. Plasma membrane calcium-ATPase activity was reduced to 79.8% and 55.7% of control values at 1 h and 6 h, respectively, following the administration of acetaminophen. No inhibition of this enzyme was detected in mice receiving 3'-hydroxyacetanilide. Acetaminophen also induced alterations in mitochondrial calcium levels and decreased the ability of isolated mitochondria to sequester calcium. These effects were not produced by 3'-hydroxyacetanilide. Our results indicate that acetaminophen induces alterations in calcium homeostasis while 3'-hydroxyacetanilide does not.
对禁食的、经苯巴比妥诱导的小鼠腹腔注射对乙酰氨基酚（250毫克/千克）会产生肝毒性。给予区域异构体3'-羟基乙酰苯胺（600毫克/千克）后未观察到肝毒性。在这些剂量下，接受对乙酰氨基酚或3'-羟基乙酰苯胺的小鼠与肝匀浆的共价结合水平相似。然而，亚细胞分级分离技术显示，对乙酰氨基酚处理比对3'-羟基乙酰苯胺产生更高水平的与线粒体蛋白的共价结合。此外，对乙酰氨基酚比对3'-羟基乙酰苯胺更广泛地消耗线粒体谷胱甘肽水平。腹腔注射对乙酰氨基酚后，质膜钙-ATP酶活性在1小时和6小时分别降至对照值的79.8%和55.7%。在接受3'-羟基乙酰苯胺的小鼠中未检测到该酶的抑制作用。对乙酰氨基酚还诱导线粒体钙水平发生改变，并降低分离线粒体隔离钙的能力。这些效应不是由3'-羟基乙酰苯胺产生的。我们的结果表明，对乙酰氨基酚会诱导钙稳态改变，而3'-羟基乙酰苯胺则不会。
