Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells.
Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polymerase and cause termination of synthesis of growing mtDNA strands and mtDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human muscle biopsies, were exposed to various concentrations of AZT (4-5000 micromol/l), ddI (5-1000 micromol/l) and ddC (1-1000 micromol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipid droplet accumulation, lactate production and respiratory chain enzyme activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent inhibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic lipid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (complex I) and citrate sinthase activities were unchanged. Zalcitabine (ddC) and, to a lesser extent, ddI, were the most potent inhibitors of mitochondrial function. In conclusion, AZT, ddI and ddC all exert cytotoxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy in HIV-infected patients. AZT myopathy might not simply result from a direct mitochondrial toxic effect of crude AZT.
Benbrik
E
E
Groupe d'Etudes et de Recherches sur le Muscle et le Nerf (GERMEN: ER 269 et 315, Université Paris XII), Faculté de Médecine, Créteil, France.
Chariot
P
P
Bonavaud
S
S
Ammi-Saïd
M
M
Frisdal
E
E
Rey
C
C
Gherardi
R
R
Barlovatz-Meimon
G
G
D019380:Anti-HIV Agents / Q000633:toxicity*; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D016049:Didanosine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D050356:Lipid Metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors; D010088:Oxidoreductases / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D016047:Zalcitabine / Q000633:toxicity*; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D007773:Lactates; D009097:Multienzyme Complexes; D019384:Nucleic Acid Synthesis Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D003576:Electron Transport Complex IV; D016049:Didanosine