Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms

doi:10.1021/acs.chemrestox.5b00290

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	Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms
	Zhou, Lei; Pang, Xiaoyan; Xie, Cen; Zhong, Dafang; Chen, Xiaoyan
刊名	CHEMICAL RESEARCH IN TOXICOLOGY
	2015-12
卷号	28 期号:12 页码:2267-2277
ISSN号	0893-228X
DOI	10.1021/acs.chemrestox.5b00290
文献子类	Article
英文摘要	Nimesulide (NIM) is a nonsteroidal anti-inflammatory drug, and clinical treatment with NIM has been associated with severe hepatotoxicity. The bioactivation of nitro-reduced NIM (NIM-NH2), a major NIM metabolite, has been thought to be responsible for the hepatotoxicity of NIM. However, we found that NIM-NH, did not induce toxic effects in primary rat hepatocytes. This study aimed to investigate other bioactivation pathways of NIM and evaluate their association with hepatotoxicity. After incubating NIM with NADPH- and GSH-supplemented human or rat liver microsomes, we identified two types of GSH conjugates: one was derived from the attachment of GSH to NIM-NH2 (NIM-NH2-GSH) and the other one was derived from a quinone-imine intermediate (NIM-OH-GSH). NIM-NH2-GSH was generated not only by the oxidative activation of NIM-NH2 but also from the reductive activation of NIM. Both NADPH and GSH could act as reducing agents. Moreover, aldehyde oxidase also participated in the reductive activation of NIM. NIM-OH-GSH was generated mainly from NIM via epoxidation with CYP1A2 as the main catalyzing enzyme. MM was toxic to both primary human and rat hepatocytes, with IC50 values of 213 and 40 mu M, respectively. Inhibition of the oxidative and reductive activation of NIM by the nonspecific CYP inhibitor 1-aminobenzotriazole and selective aldehyde oxidase inhibitor estradiol did not protect the cells from NIM-mediated toxicity. Moreover, pretreating cells with L-buthionine-sulfoximine (a GSH depletor) did not affect the cytotoxicity of NIM. These results suggested that oxidative and reductive activation of NIM did not cause the hepatotoxicity and that the parent drug concentration was associated with the cytotoxicity.
资助项目	National Natural Science Foundation of China[81573500]
WOS关键词	ISOLATED RAT HEPATOCYTES ; S-TRANSFERASE ACTIVITY ; INDUCED LIVER-INJURY ; METABOLIC-ACTIVATION ; INDUCED HEPATOTOXICITY ; ALDEHYDE OXIDASE ; BIOACTIVATION ; INHIBITOR ; TOXICITY ; ACETAMINOPHEN
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Toxicology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000367118000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276300]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Lei,Pang, Xiaoyan,Xie, Cen,et al. Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2015,28(12):2267-2277.
APA	Zhou, Lei,Pang, Xiaoyan,Xie, Cen,Zhong, Dafang,&Chen, Xiaoyan.(2015).Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms.CHEMICAL RESEARCH IN TOXICOLOGY,28(12),2267-2277.
MLA	Zhou, Lei,et al."Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms".CHEMICAL RESEARCH IN TOXICOLOGY 28.12(2015):2267-2277.