9-Glutathiony1-6,7-dihydro-1-hydroxymethy1-5H-pyrrolizine Is the Major Pyrrolic Glutathione Conjugate of Retronecine-Type Pyrrolizidine Alkaloids in Liver Microsomes and in Rats

被引：32

作者：

Chen, Meixia ^{[1
]}

Li, Liang ^{[1
]}

Zhong, Dafang ^{[1
]}

Shen, Shuijie ^{[2
]}

Zheng, Jiang ^{[2
,3
]}

Chen, Xiaoyan ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai, Peoples R China

[2] Univ Washington, Dept Pediat, Div Gastroenterol & Hepatol, Ctr Dev Therapeut,Seattle Childrens Res Inst, Seattle, WA 98195 USA

[3] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, Shenyang, Peoples R China

来源：

CHEMICAL RESEARCH IN TOXICOLOGY | 2016年 / 29卷 / 02期

基金：

中国国家自然科学基金;

关键词：

DNA-ADDUCTS; METABOLIC-ACTIVATION; SPECIES-DIFFERENCES; C-14; MONOCROTALINE; MASS-SPECTROMETRY; IN-VITRO; CLIVORINE; TOXICITY; TUMORIGENICITY; HEPATOTOXICITY;

D O I：

10.1021/acs.chemrestox.5b00427

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Retronecine-, otonecine-, and heliotridine-type pyrrolizidine alkaloids (PAs) are all reported to be hepatotoxic. These PAs are suggested to be metabolized to the corresponding electrophilic dehydropyrrolizidine alkaloids (dehydro-PAs) and subsequently conjugated with macromolecules, such as glutathione (GSH). In the present study, a total of five glutathione conjugates, named M1-M5, were detected in rat and human liver microsomal incubations with three retrornecine-type PAs (isoline, retrorsine, or monocrotaline) in the presence of glutathione, and were chemically synthesized. M1 and M3 were unambiguously identified as a pair of epimers of 7-glutathionyl-6,7-dihydro-1-hydroxymethyl-SH-pyrrolizine (7-GSH-DHP), and M4 and MS were epimers of 7,9-diglutathiony1-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (7,9-diGSH-DHP). M2, an extremely unstable conjugate, was proposed to be 9-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (9-GSH-DHP). It was the most abundant among the five GSH conjugates, and the finding corrects the mistake that 7-GSH-DHP is the predominant GSH conjugate derived from dehydro-PAs. Similar patterns in glutathione conjugate profile were observed in the bile of rats treated with the PAs. This is the first study to describe 9-GSH-DHP as a major pyrrolic GSH conjugate of retronecine-type PAs, providing insight into the interactions of dehydro-PAs with biomolecules.

引用

页码：180 / 189

页数：10

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