Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity

doi:10.1080/00498254.2021.1961920

	Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity
	Sun, Dongxue 1,2; Gao, Xiaoxia 2,3; Wang, Qiao 4; Krausz, Kristopher W.2; Fang, Zhongze 2,5; Zhang, Youbo 2,6,7; Xie, Cen 2,8; Gonzalez, Frank J.2
刊名	XENOBIOTICA
	2021-08-07
页码	13
关键词	CYP podophyllotoxin metabolism liver microsomes recombinant drug-metabolizing enzymes hepatic and intestinal toxicity
ISSN号	0049-8254
DOI	10.1080/00498254.2021.1961920
通讯作者	Zhang, Youbo(ybzhang@bjmu.edu.cn) ; Xie, Cen(xiecen@simm.ac.cn) ; Gonzalez, Frank J.(gonzalef@mail.nih.gov)
英文摘要	Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo. Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns. Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5. POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities. This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
资助项目	National Cancer Institute Intramural Research Program
WOS关键词	CATALYZED METABOLISM ; QUINONE METABOLITE ; COVALENT BINDING ; ETOPOSIDE ; CONSTITUTION ; BIOACTIVATION ; INFLAMMATION ; INHIBITION ; MECHANISMS ; COMPONENTS
WOS研究方向	Pharmacology & Pharmacy ; Toxicology
语种	英语
出版者	TAYLOR & FRANCIS LTD
WOS记录号	WOS:000683306900001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298156]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Youbo; Xie, Cen; Gonzalez, Frank J.
作者单位	1.Shenyang Pharmaceut Univ, Coll Tradit Chinese Med, Shenyang, Liaoning, Peoples R China 2.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA 3.Shanxi Univ, Modern Res Ctr Tradit Chinese Med, Taiyuan, Shanxi, Peoples R China 4.Hebei Med Univ, Sch Pharm, Shijiazhuang, Hebei, Peoples R China 5.Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin, Peoples R China 6.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China 7.Peking Univ, Sch Pharmaceut Sci, Dept Nat Med, Beijing 100191, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Sun, Dongxue,Gao, Xiaoxia,Wang, Qiao,et al. Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity[J]. XENOBIOTICA,2021:13.
APA	Sun, Dongxue.,Gao, Xiaoxia.,Wang, Qiao.,Krausz, Kristopher W..,Fang, Zhongze.,...&Gonzalez, Frank J..(2021).Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity.XENOBIOTICA,13.
MLA	Sun, Dongxue,et al."Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity".XENOBIOTICA (2021):13.