Assessment of mitochondrial toxicity induced by zidovudine and adefovir dipivoxil in rats

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 (125mg/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 mitoehondria 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.Conclusion 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 rnitochondrial toxic effects. Key words: Mitochondria;  Cytochrome c oxidase;  Zidovudine;  Adefovir dipivoxil