Uetrecht J, Zahid N, Rubin R
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Chem Res Toxicol. 1988 Jan-Feb;1(1):74-8. doi: 10.1021/tx00001a013.
The chronic use of procainamide is associated with a high incidence of drug-induced lupus and also agranulocytosis. We have previously demonstrated that procainamide is metabolized in the liver to reactive hydroxylamine (PAHA) and nitroso (nitroso-PA) metabolites which covalently bind to protein and are toxic to lymphocytes. We proposed that these metabolites were responsible for the toxicities of procainamide. However, PAHA and nitroso-PA do not appear to escape the liver in significant concentrations. In this paper we describe the metabolism of procainamide to a reactive hydroxylamine by neutrophils and mononuclear leukocytes. Such metabolism only occurs if the cells have been stimulated to have a respiratory burst. These observations have obvious possible implications for the mechanism of procainamide-induced agranulocytosis (formation of a reactive metabolite by neutrophils) and procainamide-induced lupus (formation of a reactive metabolite by monocytes). The metabolism of drugs to reactive metabolites by monocytes may be a general mechanism for hypersensitivity reactions because monocytes play a key role in the processing of antigen and stimulation of antibody synthesis.
长期使用普鲁卡因胺与药物性狼疮的高发生率以及粒细胞缺乏症有关。我们之前已经证明，普鲁卡因胺在肝脏中代谢为具有反应活性的羟胺（PAHA）和亚硝基（亚硝基 - PA）代谢产物，这些代谢产物会与蛋白质共价结合并对淋巴细胞有毒性。我们推测这些代谢产物是普鲁卡因胺毒性的原因。然而，PAHA和亚硝基 - PA似乎不会以显著浓度从肝脏中逸出。在本文中，我们描述了中性粒细胞和单核白细胞将普鲁卡因胺代谢为具有反应活性的羟胺的过程。只有当细胞被刺激产生呼吸爆发时，这种代谢才会发生。这些观察结果对普鲁卡因胺诱导的粒细胞缺乏症（中性粒细胞形成反应性代谢产物）和普鲁卡因胺诱导的狼疮（单核细胞形成反应性代谢产物）的机制具有明显的潜在意义。单核细胞将药物代谢为反应性代谢产物可能是超敏反应的一种普遍机制，因为单核细胞在抗原处理和抗体合成刺激中起关键作用。
