Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids

doi:10.1007/s00204-019-02499-2

	Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids
	Yang, Mengbi 3,4,5; Ma, Jiang 3,4,5; Ruan, Jianqing 3,4,5; Ye, Yang 2,4,5; Fu, Peter Pi-Cheng 1; Lin, Ge 3,4,5
刊名	ARCHIVES OF TOXICOLOGY
	2019-08-01
卷号	93 期号:8 页码:2197-2209
关键词	Pyrrolizidine alkaloid N-oxides Pyrrolizidine alkaloids Pyrrolizidine alkaloid N-oxide toxicity Biotransformation of pyrrolizidine alkaloid N-oxides Microbiota biotransformation
ISSN号	0340-5761
DOI	10.1007/s00204-019-02499-2
通讯作者	Lin, Ge(linge@cuhk.edu.hk)
英文摘要	Pyrrolizidine alkaloids (PAs) are among the most significant groups of phytotoxins present in more than 6000 plants in the world. Hepatotoxic retronecine-type PAs and their corresponding N-oxides usually co-exist in plants. Although PA-induced hepatotoxicity is known for a long time and has been extensively studied, the toxicity of PA N-oxide is rarely investigated. Recently, we reported PA N-oxide-induced hepatotoxicity in humans and rodents and also suggested the association of such toxicity with metabolic conversion of PA N-oxides to the corresponding toxic PAs. However, the detailed biochemical mechanism of PA N-oxide-induced hepatotoxicity is largely unknown. The present study investigated biotransformation of four representative cyclic retronecine-type PA N-oxides to their corresponding PAs in both gastrointestinal tract and liver. The results demonstrated that biotransformation of PA N-oxides to PAs was mediated by both intestinal microbiota and hepatic cytochrome P450 monooxygenases (CYPs), in particular CYP1A2 and CYP2D6. Subsequently, the formed PAs were metabolically activated predominantly by hepatic CYPs to form reactive metabolites exerting hepatotoxicity. Our findings delineated, for the first time, that the metabolism-mediated mechanism of PA N-oxide intoxication involved metabolic reduction of PA N-oxides to their corresponding PAs in both intestine and liver followed by oxidative bioactivation of the resultant PAs in the liver to generate reactive metabolites which interact with cellular proteins leading to hepatotoxicity. In addition, our results raised a public concern and also encouraged further investigations on potentially remarkable variations in PA N-oxide-induced hepatotoxicity caused by significantly altered intestinal microbiota due to individual differences in diets, life styles, and medications.
资助项目	Research Grant Council of Hong Kong[14110714] ; Research Grant Council of Hong Kong[14111816]
WOS关键词	METABOLIC-ACTIVATION ; GASTROINTESTINAL-TRACT ; RAT-LIVER ; IN-VITRO ; HEPATOTOXICITY ; PLANTS ; TUMORIGENICITY ; RETRONECINE ; REDUCTION ; ZONATION
WOS研究方向	Toxicology
语种	英语
出版者	SPRINGER HEIDELBERG
WOS记录号	WOS:000483690200008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288715]
专题	中国科学院上海药物研究所
通讯作者	Lin, Ge
作者单位	1.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA 2.Chinese Acad Sci, Nat Prod Chem Dept, Shanghai Inst Mat Med, Shanghai, Peoples R China 3.Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Shatin, Hong Kong, Peoples R China 4.Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Yang, Mengbi,Ma, Jiang,Ruan, Jianqing,et al. Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids[J]. ARCHIVES OF TOXICOLOGY,2019,93(8):2197-2209.
APA	Yang, Mengbi,Ma, Jiang,Ruan, Jianqing,Ye, Yang,Fu, Peter Pi-Cheng,&Lin, Ge.(2019).Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids.ARCHIVES OF TOXICOLOGY,93(8),2197-2209.
MLA	Yang, Mengbi,et al."Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids".ARCHIVES OF TOXICOLOGY 93.8(2019):2197-2209.