title: Effects of hydroxysafflor yellow A on the activity and mRNA expression of four CYP isozymes in rats.
abstract: BACKGROUND
  In traditional therapy with Chinese medicine, hydroxysafflor yellow A (HSYA), a main active component isolated from the dried flower of Carthamus tinctorius L., is the principal efficiency ingredient of Safflor Yellow Injection. Now HSYA has been demonstrated to have good pharmacological activities of antioxidation, myocardial and cerebral protective and neuroprotective effects. The purpose of this study was to find out whether HSYA influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D4 and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied.
  
  
  METHODS
  A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), dextromethorphan (20 mg/kg) and midazolam (10 mg/kg), was given as oral administration to rats treated with short or long period of intravenous HSYA via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effect of HSYA on the mRNA expression of CYP1A2, CYP2C11, CYP2D4 and CYP3A1 in rat liver.
  
  
  RESULTS
  HSYA had significant inhibition effects on CYP1A2 and CYP2C11 in rats as oriented from the pharmacokinetic profiles of the probe drugs. Furthermore, HSYA had no effects on rat CYP2D4. However, CYP3A1 enzyme activity was induced by HSYA. The mRNA expression results were in accordance with the pharmacokinetic results.
  
  
  CONCLUSIONS
  HSYA can either inhibit or induce activities of CYP1A2, CYP2C11 and CYP3A1. Therefore, co-administration of some CYP substrates with HSYA may need dose adjustment to avoid an undesirable herb-drug interaction.
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Ren-Ai
authors.initials: RA
authors.lastname: Xu
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: 15088554595@163.com.
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
mesh_terms: D000818:Animals; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003915:Dextromethorphan / Q000097:blood / Q000493:pharmacokinetics; D041743:Herb-Drug Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D010615:Phenacetin / Q000097:blood / Q000493:pharmacokinetics; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011809:Quinones; D012333:RNA, Messenger; C085278:hydroxysafflor yellow A; D002599:Chalcone; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D010615:Phenacetin; D008874:Midazolam
keywords: CYP; Carbamazepine (PubChem CID: 2554); Cocktail; Dextromethorphan (PubChem CID: 5360696); Hydroxysafflor yellow A; Hydroxysafflor yellow A (PubChem CID: 6443665); Midazolam (PubChem CID: 4192); Phenacetin (PubChem CID: 4754); Probe drugs; Real-time RT-PCR; Tolbutamide (PubChem CID: 5505); mRNA