MECHANISMS OF DRUG-INDUCED TOXICITIES

药物引起的毒性机制

• 批准号: 6162673
• 负责人: Lance R Pohl
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162673
• 关键词: autoantibody; cytochrome P450; drug adverse effect; drug metabolism; halothane; hepatitis; hepatotoxin; human tissue; inhalation anesthesia; laboratory rat; liver toxic disorder; nonsteroidal antiinflammatory agent

This year we have continued our studies on the mechanisms of drug toxicities. In one study, it was discovered that a mixture of the refrigerants HCFC-123 and 124 caused an epidemic of hepatotoxicity, when workers in a smelting plant in Belgium were exposed to these chemicals. Immunohistochemical analysis of a liver biopsy from one of the workers revealed the presence of liver proteins that had been covalently altered by a toxic trifluoroacetyl halide metabolite of these chemicals. Moreover, most of the workers tested positive for P4502E1 and P58 autoantibodies, which have been associated with halothane hepatitis. The results of this study strongly indicate that exposure of humans to HCFC-123 and 124 can result in a high incidence of serious liver injury. This year we have concluded that the nephrotoxicity of Compound A (fluoromethyl-2,2-difluoro(trifluoromethyl) vinyl ether), which is a decomposition product of the inhalation anesthetic sevoflurane, is not dependent on metabolism by renal cysteine conjugate beta-lyase. This conclusion is based on the findings that an inhibitor of this enzyme did not prevent the toxicity and products of the enzymatic reaction could not be detected immunochemically in the kidney. In another study, we have found by immunochemical analyses that diclofenac and other drugs form covalent adducts in enterocytes of the small intestine of rats and mice. Since these adducts are in close proximity to the gut-associated lymphoid tissue, we believe that they may have a role in preventing drug allergies against these drugs by an oral tolerance mechanism.

今年我们继续进行药物作用机制的研究 毒性。 在一项研究中发现， 制冷剂 HCFC-123 和 124 引起了广泛的肝毒性，当 比利时一家冶炼厂的工人接触了这些化学物质。 对一名工人的肝活检进行免疫组织化学分析 揭示了共价改变的肝脏蛋白质的存在 由这些化学物质的有毒三氟乙酰卤代谢物引起。 此外，大多数工人的 P4502E1 和 P58 检测呈阳性 自身抗体，与氟烷肝炎有关。 这项研究的结果强烈表明，人类暴露于 HCFC-123 和 124 可导致严重肝损伤的发生率很高。 今年我们得出结论，化合物 A 的肾毒性 （氟甲基-2,2-二氟（三氟甲基）乙烯基醚），这是 吸入麻醉剂七氟烷的分解产物，不是 依赖于肾半胱氨酸结合物β-裂合酶的代谢。 这 结论是基于这种酶的抑制剂确实 不能防止酶促反应的毒性和产物 在肾脏中不能通过免疫化学方法检测到。 在另一项研究中，我们 通过免疫化学分析发现双氯芬酸和其他药物 在大鼠小肠的肠细胞中形成共价加合物 老鼠。 由于这些加合物非常接近肠道相关的 淋巴组织，我们相信它们可能具有预防药物作用 通过口服耐受机制对这些药物过敏。