MECHANISMS OF DRUG-INDUCED TOXICITIES

一般认为，药物性过敏性肝炎是一种罕见但危及生命的药物不良反应，是由对肝组织的免疫反应引起的，这种免疫反应已被药物的反应性代谢产物不可逆地改变。 今年，我们研究了可能决定个体发生此类药物不良反应的易感性的因素。在一项研究中，我们研究了口服耐受性在预防药物诱导的过敏性肝炎中的作用，口服耐受性是由口服抗原引起的抗原特异性免疫低反应性。 虽然最近的证据表明，肝脏可能有一个作用，在诱导口服耐受性对蛋白质抗原，相对较少的工作已经做了探索肝脏的作用，在耐受性引起的口服给药的药物和其他致敏化学品。 作为解决这一问题的第一步，我们给小鼠喂食皮肤致敏剂2，4-二硝基氯苯（DNCB），然后用这种化合物致敏和激发它们。 在另一组动物中，将DNCB喂给小鼠，并使用抗二硝基苯基（DNP）半抗原的多克隆抗体通过免疫印迹法测定肝脏中DNCB的蛋白加合物。 结果发现，给小鼠喂饲DNCB可抑制DNCB的耳肿胀效应，并导致DNCB在肝细胞和肝枯否细胞中形成蛋白加合物。 由于这些细胞已被认为在诱导对蛋白抗原的口服耐受性中起作用，它们也可以抑制口服药物后在肝脏中形成的药物蛋白加合物的免疫反应。 在这方面，在其他研究中发现，当氟烷和对乙酰氨基酚的代谢物在肝脏中形成蛋白加合物时，抗炎细胞因子和其他因子，如白细胞介素4、10、11和13以及皮质醇迅速分泌到血液中。 据信，这些因子可通过防止随后的细胞介导的针对已被药物的反应性代谢物修饰的肝蛋白的免疫反应而具有保护作用。 可能发生药物性过敏性肝炎的个体在一种或多种抗炎因子的调节方面存在缺陷。

It is generally believed that drug-induced allergic hepatitis, a rare but life-threatening adverse drug reaction, is caused by an immune reaction against liver tissue that has been irreversibly altered by a reactive metabolite of a drug. This year we have investigated those factors that may determine the susceptibility of an individual to develop this type of adverse drug reaction. In one study, we investigated the role of oral tolerance, an antigen-specific immunological hyporesponsiveness induced by the oral administration of antigens, in preventing drug-induced allergic hepatitis. Although recent evidence suggests that the liver may have a role in the induction of oral tolerance against protein antigens, relatively little work has been done to explore the role of the liver in tolerance caused by the oral administration of drugs and other sensitizing chemicals. As an initial step to address this problem, we fed the skin-sensitizing agent 2,4-dinitrochlorobenzene (DNCB) to mice prior to sensitizing and challenging them with this compound. In another set of animals, DNCB was fed to mice and protein adducts of DNCB were measured in the liver immunohistochemically and by immunoblotting with the use of polyclonal antibodies raised against the dinitrophenyl (DNP) hapten. It was found that the feeding of DNCB to mice inhibited the ear swelling effects of DNCB and led to the formation of protein adducts of DNCB in hepatocytes and Kupffer cells of the liver. Since these cells have been suggested to have a role in the induction of oral tolerance against protein antigens, they may also inhibit immune reactions against protein adducts of drugs that are formed in the liver after a drug has been administered orally. In this regard, it was found in other studies that anti-inflammatory cytokines and other factors, such as interleukins 4,10, 11, and 13, and cortisol, were rapidly secreted into the blood, when metabolites of halothane and acetaminophen formed protein adducts in the liver. It is believed that these factors may have a protective role by preventing subsequent cell mediated immune reactions against liver proteins that have been modified by reactive metabolites of drugs. Perhaps individuals who develop drug-induced allergic hepatitis have a defect in the regulation of one or more of these anti-inflammatory factors.