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.