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
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.