双氟尼酸酰基葡萄糖醛酸修饰的大鼠血清白蛋白在大鼠体内具有免疫原性。

Rat serum albumin modified by diflunisal acyl glucuronide is immunogenic in rats.

作者信息

Worrall S, Dickinson R G

机构信息

Department of Biochemistry, University of Queensland, Brisbane, Australia.

出版信息

Life Sci. 1995;56(22):1921-30. doi: 10.1016/0024-3205(95)00167-5.

DOI:10.1016/0024-3205(95)00167-5

PMID:7538189

Abstract

Acyl glucuronide metabolites of carboxylic acid drugs such as the salicylate derivative diflunisal (DF) have been shown to react with proteins in vitro and in vivo to produce covalent adducts. Such attachment of foreign compounds to endogenous molecules could be associated with toxic and/or immune consequences. In this study we have injected rats with rat serum albumin (RSA) modified (a) by DF using a carbodiimide reagent (-->DF-RSA-I, 4.9 micrograms DF/mg RSA) and (b) by incubation with DF acyl glucuronide (DAG) and its rearrangement isomers (iso-DAG) (-->DF-RSA-II, 0.34 micrograms DF/mg RSA). All of the six rats injected with DF-RSA-I produced antibodies reactive with DF-modified keyhole limpet hemocyanin (KLH), the coating protein used in the ELISA. Three out of six animals injected with DF-RSA-II generated similar antibodies. Cross-reactivity with other non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ketoprofen (as the free drugs) was not observed. This study shows that a self protein covalently modified by incubation with DAG and iso-DAG is immunogenic in rats. The data thus support the hypothesis that covalent modification of macromolecules by acyl glucuronide metabolites of acidic drugs in vivo can lead to the production of circulating antibodies which may be involved in aberrant immune responses such as drug hypersensitivity.

摘要

羧酸类药物的酰基葡萄糖醛酸代谢物，如水杨酸盐衍生物二氟尼柳（DF），已证实在体外和体内均可与蛋白质发生反应，生成共价加合物。外来化合物与内源性分子的这种结合可能会产生毒性和/或免疫后果。在本研究中，我们给大鼠注射了经如下方式修饰的大鼠血清白蛋白（RSA）：（a）使用碳二亚胺试剂使RSA与DF反应（-->DF-RSA-I，4.9微克DF/毫克RSA）；（b）使RSA与DF酰基葡萄糖醛酸（DAG）及其重排异构体（异-DAG）孵育（-->DF-RSA-II，0.34微克DF/毫克RSA）。所有注射DF-RSA-I的6只大鼠均产生了与DF修饰的钥孔戚血蓝蛋白（KLH）反应的抗体，KLH是ELISA中使用的包被蛋白。注射DF-RSA-II的6只动物中有3只产生了类似抗体。未观察到与其他非甾体抗炎药（NSAIDs）如萘普生和酮洛芬（作为游离药物）的交叉反应。本研究表明，与DAG和异-DAG孵育后共价修饰的自身蛋白在大鼠中具有免疫原性。因此，这些数据支持以下假设：体内酸性药物的酰基葡萄糖醛酸代谢物对大分子的共价修饰可导致循环抗体的产生，这些抗体可能参与异常免疫反应，如药物超敏反应。