title: Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen).
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1] Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Tian
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Jia
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xin-wei
authors.initials: XW
authors.lastname: Liu
authors.affiliation: Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jun-hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia-jia
authors.initials: JJ
authors.lastname: Dong
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fei-fei
authors.initials: FF
authors.lastname: Du
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Feng-qing
authors.initials: FQ
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu-xing
authors.initials: YX
authors.lastname: Huang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mei-juan
authors.initials: MJ
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Li-hong
authors.initials: LH
authors.lastname: Hu
authors.affiliation: Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Xiu-mei
authors.initials: XM
authors.lastname: Gao
authors.affiliation: 1] Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Shanghai 201203, China [3] Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.affiliation: 1] Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jun-ling
authors.initials: JL
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002109:Caffeic Acids / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D041743:Herb-Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D007684:Kidney Tubules / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D026901:Membrane Transport Proteins / Q000378:metabolism; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D008517:Phytotherapy; D018517:Plant Roots; D010946:Plants, Medicinal; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013431:Sulfates / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D002317:Cardiovascular Agents; D004365:Drugs, Chinese Herbal; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; C421043:Slc22a6 protein, rat; D013431:Sulfates; C585969:tanshinol; D003577:Cytochrome P-450 Enzyme System; D002394:Catechol O-Methyltransferase