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Some nucleoside analogue reverse transcriptase inhibitors (NRTI) may cause depletion of mitochondrial (mt) DNA in liver by inhibiting polymerase-γ. mtDNA depletion may contribute to lactic acidosis, steatohepatitis and liver failure.To evaluate the long-term mitochondrial toxicity of NRTI combinations.The HepG2 human hepatoma cell line was cultivated in the presence of zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), zidovudine (ZDV) and efavirenz at concentrations equivalent to steady-state peak plasma levels (Cmax), and also in one-third and 10 times Cmax. The NRTI were added to the medium alone or in combination. Control cells were incubated without any NRTI or with efavirenz. Cell growth, lactate production, intracellular lipid droplets, mtDNA and the mtDNA-encoded respiratory chain subunit COX II were monitored over a period of up to 30 days.Time- and dose-dependent mtDNA depletion was observed with ddC > ddI > d4T and mtDNA depletion preceded or coincided with a decline in COX II expression, a decrease in cell growth, increased lactate production and increased intracellular lipids. 3TC and efavirenz did not affect any measurement. ZDV increased lactate moderately and cell growth was inhibited, despite normal mtDNA and COX II levels. The negative effects on some measurements were more pronounced in the 3TC–ZDV and ddC–d4T combinations, than in the single-NRTI incubations. The combination of ddI–d4T was not more toxic than ddI alone. Mitochondrial damage by ZDV, d4T, ddI, and ddC did not reach steady-state by day 25. Using a Southern blot technique, mtDNA deletions were never observed.The data indicate additive or synergistic long-term mitochondrial toxicity in some NRTI combinations.