Effects of short-term zidovudine exposure on mitochondrial DNA content and succinate dehydrogenase activity of rat skeletal muscle cells.
Long-term use of zidovudine (AZT) may cause mitochondrial abnormalities in various tissues, including a toxic myopathy in AIDS patients associated with mitochondrial DNA (mtDNA) depletion. In the present study, we examine the short-term (48 h) effect of AZT (10, 30 and 100 microg/ml) on the mitochondrial succinate dehydrogenase (SDH) and mtDNA content of rat cultured skeletal muscle. The effect of AZT on cytochrome c oxidase (COX) enzyme was also analyzed. The histochemical quantitative analysis of SDH showed that AZT 10, 30 and 100 microg/ml increased by 7%, 9% and 13% the mitochondrial content. Conversely, treatment of rat cultures with 10 to 100 microg/ml AZT reduced the mtDNA content by 23% to 66%, when compared to control values. The spontaneous contraction and the COX activity were not modified by up to 100 microg/ml AZT. Taken together, these results show that short-term treatment with AZT can induce severe myotoxicity that involves mitochondrial proliferation and mtDNA depletion in the rat cultured myotubes. Our results also indicate that rat cultured skeletal muscle might be a valuable in vitro assay to evaluate the effect of drugs on mitochondria to predict their potential to induce mitochondrial toxicity.
Department of Neurology and Neurosurgery, Universidade Federal de São Paulo - Escola Paulista de Medicina, Rua Pedro de Toledo 781, São Paulo, SP, 04039-032, Brazil.
Beatriz H
BH
Kiyomoto
Celia H
CH
Tengan
Rosely O
RO
Godinho
D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000494:pharmacology*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000166:cytology*; D051381:Rats; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D015215:Zidovudine / Q000494:pharmacology*
D000963:Antimetabolites; D004272:DNA, Mitochondrial; D015215:Zidovudine; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV