Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen)

doi:10.1038/aps.2015.20

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	Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen)
	Tian, Dan-dan 2,3; Jia, Wei-wei 2; Liu, Xin-wei 2; Wang, Dan-dan 4; Liu, Jun-hua 2; Dong, Jia-jia 2; Li, Li 2; Du, Fei-fei 2; Xu, Fang 2; Wang, Feng-qing 2
刊名	ACTA PHARMACOLOGICA SINICA
	2015-05
卷号	36 期号:5 页码:627-643
关键词	tanshinol methylation catechol-O-methyltransferase herb-drug interaction Salvia miltiorrhiza roots Danshen
ISSN号	1671-4083
DOI	10.1038/aps.2015.20
文献子类	Article
英文摘要	Aim: Tanshinol is an important catechol in the antianginal herb Salvia miltiorrhiza roots (Danshen). This study aimed to characterize tanshinol methylation. Methods: Metabolites of tanshinol were analyzed by liquid chromatography/mass spectrometry. Metabolism was assessed in vitro with rat and human enzymes. The major metabolites were synthesized for studying their interactions with drug metabolizing enzymes and transporters and their vasodilatory properties. Dose-related tanshinol methylation and its influences on tanshinol pharmacokinetics were also studied in rats. Results: Methylation, preferentially in the 3-hydroxyl group, was the major metabolic pathway of tanshinol. In rats, tanshinol also underwent considerable 3-O-sulfation, which appeared to be poor in human liver. These metabolites were mainly eliminated via renal excretion, which involved tubular secretion mainly by organic anion transporter (OAT) 1. The methylated metabolites had no vasodilatory activity. Entacapone-impaired methylation did not considerably increase systemic exposure to tanshinol in rats. The saturation of tanshinol methylation in rat liver could be predicted from the Michaelis constant of tanshinol for catechol-O-methyltransferase (COMT). Tanshinol had low affinity for human COMT and OATs; its methylated metabolites also had low affinity for the transporters. Tanshinol and its major human metabolite (3-O-methyltanshinol) exhibited negligible inhibitory activities against human cytochrome P450 enzymes, organic anion transporting polypeptides 1B1/1B3, multidrug resistance protein 1, multidrug resistance-associated protein 2, and breast cancer resistance protein. Conclusion: Tanshinol is mainly metabolized via methylation. Tanshinol and its major human metabolite have low potential for pharmacokinetic interactions with synthetic antianginal agents. This study will help define the risk of hyperhomocysteinemia related to tanshinol methylation.
资助项目	National Natural Science Foundation of China for Distinguished Young Scholars[30925044] ; National Science & Technology Major Project of China 'Key New Drug Creation and Manufacturing Program'[2009ZX09304-002] ; National Basic Research Program of China[2012CB518403]
WOS关键词	HERB-DRUG INTERACTIONS ; O-METHYLTRANSFERASE ; PLASMA HOMOCYSTEINE ; PARKINSONS-DISEASE ; CYTOSOLIC SULFOTRANSFERASE ; ENDOTHELIAL DYSFUNCTION ; MOLECULAR-MECHANISMS ; DANHONG INJECTION ; SYSTEMIC EXPOSURE ; AQUEOUS EXTRACT
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000353893100010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276554]
专题	上海药物代谢研究中心科研与新药推进处
通讯作者	Li, Chuan
作者单位	1.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Shanghai 201203, Peoples R China; 4.Tianjin Univ Tradit Chinese Med, Tianjin 300193, Peoples R China;
推荐引用方式 GB/T 7714	Tian, Dan-dan,Jia, Wei-wei,Liu, Xin-wei,et al. Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen)[J]. ACTA PHARMACOLOGICA SINICA,2015,36(5):627-643.
APA	Tian, Dan-dan.,Jia, Wei-wei.,Liu, Xin-wei.,Wang, Dan-dan.,Liu, Jun-hua.,...&Yang, Jun-ling.(2015).Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen).ACTA PHARMACOLOGICA SINICA,36(5),627-643.
MLA	Tian, Dan-dan,et al."Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen)".ACTA PHARMACOLOGICA SINICA 36.5(2015):627-643.