title: Kinetics of cytochrome P450 enzymes for metabolism of sodium tanshinone IIA sulfonate in vitro.
abstract: BACKGROUND
  Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA for treating cardiovascular disorders. The roles of cytochrome P450 enzymes (CYPs) in the metabolism of STS have remained unclear. This study aims to screen the main CYPs for metabolism of STS and study their interactions in vitro.
  
  
  METHODS
  Seven major CYPs were screened for metabolism of STS by human liver microsomes (HLMs) or recombinant CYP isoforms. Phenacetin (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), metoprolol (CYP2D6), chlorzoxazone (CYP2E1), S-mephenytoin (CYP2C19), and midazolam (CYP3A4) were used as probe substrates to determine the potential of STS in affecting CYP-mediated phase I metabolism in humans. Enzyme kinetic studies were performed to investigate the modes of inhibition of the enzyme-substrate interactions by GraphPad Prism Enzyme Kinetic 5 Demo software.
  
  
  RESULTS
  Sodium tanshinone IIA sulfonate inhibited the activity of CYP3A4 in a dose-dependent manner by the HLMs and CYP3A4 isoform. The K m and V max values of STS were 54.8 ± 14.6 µM and 0.9 ± 0.1 nmol/mg protein/min, respectively, for the HLMs and 7.5 ± 1.4 µM and 6.8 ± 0.3 nmol/nmol P450/min, respectively, for CYP3A4. CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP2C19 showed minimal or no effects on the metabolism of STS.
  
  
  CONCLUSIONS
  This in vitro study showed that STS mainly inhibited the activities of CYP3A4.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China ; Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Ouyang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Huang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Tan
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Jing-Bo
authors.initials: JB
authors.lastname: Peng
authors.affiliation: Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Dong-Li
authors.initials: DL
authors.lastname: Hu
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China ; Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, 410078 Hunan China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen