title: Protective effect of 23-hydroxybetulinic acid on doxorubicin-induced cardiotoxicity: a correlation with the inhibition of carbonyl reductase-mediated metabolism.
abstract: OBJECTIVE
  The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. 23-Hydroxybetulinic acid (23-HBA), isolated from Pulsatilla chinensis, enhances the anticancer effect of doxorubicin while simultaneously reducing its cardiac toxicity, but does not affect the concentration of doxorubicin in the plasma and heart. As the metabolite doxorubicinol is more potent than doxorubicin at inducing cardiac toxicity, in the present study we aimed to clarify the role of doxorubicinol in the protective effect of 23-HBA.
  
  
  METHODS
  Doxorubicin was administered to mice for two weeks in the presence or absence of 23-HBA. The heart pathology, function, myocardial enzymes and accumulation of doxorubicin and doxorubicinol were then analysed. A cellular pharmacokinetic study of doxorubicin and doxorubicinol, carbonyl reductase 1 (CBR1) interference and molecular docking was performed in vitro.
  
  
  RESULTS
  23-HBA alleviated the doxorubicin-induced cardiotoxicity in mice, and this was accompanied by inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts. In H9c2 cells, the protective effect of 23-HBA was shown to be closely associated with a decreased rate and extent of accumulation of doxorubicinol in mitochondria and nuclei. siRNA and docking analysis demonstrated that CBR1 has a crucial role in doxorubicin-mediated cardiotoxicity and 23-HBA inhibits this metabolic pathway.
  
  
  CONCLUSIONS
  Inhibition of CBR-mediated doxorubicin metabolism might be one of the protective mechanisms of 23-HBA against doxorubicin-induced cardiotoxicity. The present study provides a new research strategy guided by pharmacokinetic theory to elucidate the mechanism of drugs with unknown targets.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.|Suzhou Institute for Food and Drug Control, Suzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hao
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Hao
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Niu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Luo
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ye
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.|Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D051381:Rats; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C468651:23-hydroxybetulinic acid; D004791:Enzyme Inhibitors; D014315:Triterpenes; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C010013:adriamycinol