title: Doxorubicin toxicity changes myocardial energy metabolism in rats.
abstract: BACKGROUND
  Doxorubicin (DOX) is an antitumor antibiotics used against malignancies. But its toxicity limits the therapy of DOX.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate DOX toxicity and the alteration of energy metabolism after short term and long term treatment.
  
  
  METHODS
  Male Sprague-Dawley rats were randomly assigned to four groups: Short term control group, short term DOX treatment group, long term control group and long term DOX treatment group. In short term treated group, rats were injected with DOX i.p. at a dose of 2.5 mg/kg every 48 h for six equal injections. In long term, treated group, rats were tail-intravenously injected with DOX at a dose of 3 mg/kg once a week for four weeks. At the end of the experiment, histopathological changes, general blood biomarkers, endogenous antioxidant enzymes, cardiac energy metabolism and related mRNA expression of AMPK signal pathway were determined.
  
  
  RESULTS
  DOX induced prominent oxidative stress, a higher mortality rate, histological and ECG changes, obvious cardiac hypertrophy, acute cardiac damage and cardiac energy impairment in short term treatment rats. In long term treatment rats, DOX caused serious nephropathy and systolic dysfunction, terrible cardiac energy impairment, clear alteration of substrate utilization and AMPK signal pathway.
  
  
  CONCLUSIONS
  DOX treatment can induce different damages after short term and long term treatment. In short term treatment group, rats experienced a terrible mortality rate about 40%, the acute cardiac damage, cardiac energy impairment and an early heart failure which are potential connected with reduction of glucose utilization. In the long term treatment group, serious nephropathy and obvious changes of mRNA expressions of AMPK signal pathway were observed. Meanwhile, the serious cardiac energy impairment and substrate utilization alteration denote an obviously heart failure. This study could be helpful to develop therapy strategies of DOX complications for clinical application.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Wang
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Hai-Lun
authors.initials: HL
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Meng-Ting
authors.initials: MT
authors.lastname: Xu
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zydgjp@aliyun.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Gao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004317:Doxorubicin
keywords: AMPKα2; Doxorubicin; Myocardial energy metabolism; Toxicity