title: [Assessment of mitochondrial toxicity induced by zidovudine and adefovir dipivoxil in rats].
abstract: OBJECTIVE
  To explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.
  
  
  METHODS
  Twelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope.
  
  
  RESULTS
  No significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats.
  
  
  CONCLUSIONS
  Significant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.
authors.affiliation: Department of Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.forename: Zhen-ni
authors.initials: ZN
authors.lastname: Zhu
authors.forename: Jun-zhong
authors.initials: JZ
authors.lastname: Wang
authors.forename: Shun-mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Xue-mei
authors.initials: XM
authors.lastname: Feng
authors.forename: An-yi
authors.initials: AY
authors.lastname: Li
authors.forename: Dong-liang
authors.initials: DL
authors.lastname: Yang
authors.forename: Bao-ju
authors.initials: BJ
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D004272:DNA, Mitochondrial / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D063065:Organophosphonates / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015215:Zidovudine / Q000009:adverse effects*
chemical_list: D004272:DNA, Mitochondrial; D063065:Organophosphonates; D015215:Zidovudine; D003576:Electron Transport Complex IV; D000225:Adenine; C106812:adefovir dipivoxil