MECHANISMS OF DRUG-INDUCED TOXICITIES

今年，我们继续研究药物的作用机制， 毒性 在一项研究中，人们发现， 制冷剂HCFC-123和124引起肝毒性流行， 比利时一家冶炼厂的工人接触了这些化学品。 其中一名工人的肝活检的免疫组织化学分析 显示了肝脏蛋白质的存在， 有毒的三氟乙酰卤代谢物所导致 此外，大多数工人的P4502 E1和P58检测呈阳性 自身抗体，这与氟烷肝炎有关。 这项研究的结果有力地表明，人类暴露于 HCFC-123和124可导致严重肝损伤的高发生率。 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），其为 吸入麻醉剂七氟烷的分解产物，不是 依赖于肾半胱氨酸缀合物β-裂解酶的代谢。 这 结论是基于这样的发现，即这种酶的抑制剂 不能防止酶反应的毒性和产物， 在肾脏中未被免疫化学检测到。 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， 小鼠 由于这些加合物与肠道相关的 淋巴组织，我们认为它们可能在预防药物 通过口服耐受机制对这些药物过敏。

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.