Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4

doi:10.1021/tx5002145

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	Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4
	Yu, Jinghua; Deng, Pan; Zhong, Dafang; Chen, Xiaoyan
刊名	CHEMICAL RESEARCH IN TOXICOLOGY
	2014-09
卷号	27 期号:9 页码:1598-1609
ISSN号	0893-228X
DOI	10.1021/tx5002145
文献子类	Article
英文摘要	Toosendanin (TSN) is a hepatotoxic triterpenoid extracted from Melia toosendan Sieb et Zucc. Considering that TSN contains the structural alert of the furan ring, it is believed that bioactivation of TSN may be responsible for its toxicity. Herein, the bioactivation potential and metabolism profiles of TSN were investigated. After an oral administration of 10 mg/kg TSN to rats, esterolysis and conjugation with amino acids were identified as the main metabolic pathways. The same types of conjugates were detected in liver microsomes in an NADPH-dependent manner. According to the remaining amount of the parent drug, the reactivity of trapping reagents with TSN reactive metabolites was sorted in a decreasing order of N-alpha-(tert-butoxycarbonyl)-l-lysine (Boc-Lys) > alanine, lysine, taurine, phenylalanine, serine, glutamic acid, glycine, and glutathione (GSH) > cysteine. No conjugates were observed in NADPH and N-acetyl cysteine (NAC)-supplemented human liver microsomal incubations. Further phenotyping studies and the chemical synthesis of the major conjugated standards proved that TSN was bioactivated by CYP3A4 and yielded a cis-butene-1,4-dial intermediate, which was prone to undergo 1,2-addition with the amino group of amino acids and GSH to form 3-pyrroline-2-one adducts. The sulfydryl group of GSH also attacked the intermediate and yielded S-conjugates by 1,4- or 1,2-addition, which would form pyrrole conjugates by further reacting with the amino group. Compared to the well-recognized S-conjugation of the furan ring, N-conjugation with multiple amino acids and GSH played a more important part in the elimination of reactive metabolites of TSN. The significance of these conjugates requires further investigation.
资助项目	National Natural Science Foundation of China[81202579] ; National Natural Science Foundation of China[81173115]
WOS关键词	REACTIVE METABOLITE ; TEUCRIN-A ; IN-VITRO ; (R)-(+)-MENTHOFURAN ; ACTIVATION ; ADDUCTS ; VIVO ; RATS
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Toxicology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000341747600014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276918]
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	Yu, Jinghua,Deng, Pan,Zhong, Dafang,et al. Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2014,27(9):1598-1609.
APA	Yu, Jinghua,Deng, Pan,Zhong, Dafang,&Chen, Xiaoyan.(2014).Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4.CHEMICAL RESEARCH IN TOXICOLOGY,27(9),1598-1609.
MLA	Yu, Jinghua,et al."Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4".CHEMICAL RESEARCH IN TOXICOLOGY 27.9(2014):1598-1609.