CELLULAR AND MITOCHONDRIAL TOXICITY OF ZIDOVUDINE (AZT), DIDANOSINE (DDI) AND ZALCITABINE (DDC) ON CULTURED HUMAN MUSCLE-CELLS

Citation
E. Benbrik et al., CELLULAR AND MITOCHONDRIAL TOXICITY OF ZIDOVUDINE (AZT), DIDANOSINE (DDI) AND ZALCITABINE (DDC) ON CULTURED HUMAN MUSCLE-CELLS, Journal of the neurological sciences, 149(1), 1997, pp. 19-25
Citations number
43
Categorie Soggetti
Neurosciences
ISSN journal
0022510X
Volume
149
Issue
1
Year of publication
1997
Pages
19 - 25
Database
ISI
SICI code
0022-510X(1997)149:1<19:CAMTOZ>2.0.ZU;2-O
Abstract
Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the refer ence antiretroviral therapy in patients with AIDS. A toxic mitochondri al myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polyme rase and cause termination of synthesis of growing mtDNA strands and m tDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human mu scle biopsies, were exposed to various concentrations of AZT (4-5000 m u mol/l), ddI (5-1000 mu mol/l) and ddC (1-1000 mu mol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipi d droplet accumulation, lactate production and respiratory chain enzym e activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent in hibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic li pid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (co mplex 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 cyto toxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA d epletion. Our results provide only a partial explanation of the fact t hat AZT, but not ddI and ddC, can induce a myopathy in HIV-infected pa tients. AZT myopathy might not simply result from a direct mitochondri al toxic effect of crude AZT. (C) 1997 Elsevier Science B.V.