MECHANISMS OF DRUG-INDUCED TOXICITIES

点击翻译按钮获取中文摘要

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.