MECHANISMS OF DRUG-INDUCED TOXICITIES

今年我们继续研究药物的作用机制。 毒物。在一项研究中，人们发现一种混合的 制冷剂HCFC-123和124导致了肝毒性的流行，当 比利时一家冶炼厂的工人接触到了这些化学物质。 其中一名工人肝脏活检的免疫组织化学分析 显示存在被共价改变的肝脏蛋白质 由这些化学物质的有毒的三氟乙酰卤化物代谢物。 此外，大多数工人的P4502E1和P58检测呈阳性 与氟烷性肝炎有关的自身抗体。 这项研究的结果强烈表明，人类暴露在 氟氯烃-123和124可导致严重肝损伤的高发。 今年我们得出的结论是，化合物A的肾毒性 (氟甲基-2，2-二氟(三氟甲基)乙烯基醚)，是一种 吸入麻醉剂七氟醚的分解产物，不是 依赖于肾脏半胱氨酸结合β-裂解酶的代谢。这 结论是基于这种酶的一种抑制剂的发现 不能防止毒性和产物的酶促反应 在肾脏中免疫化学检测不到。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 在大鼠小肠细胞内形成共价加合物 老鼠。因为这些加合物非常接近肠道相关的 淋巴组织，我们认为它们可能有预防毒品的作用 对这些药物的过敏是通过口服耐受机制实现的。

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.