Major growth reduction and minor decrease in mitochondrial enzyme activity in cultured human muscle cells after exposure to zidovudine.
Zidovudine-induced mitochondrial myopathy in AIDS patients reported recently might be due to inhibition of mitochondrial DNA polymerase gamma. We investigated the effect of zidovudine on proliferation, differentiation, activity of mitochondrial- and nuclear-encoded enzymes, and mitochondrial DNA (mtDNA), in cultured human muscle cells. Marked inhibition of cell proliferation was found, even in the presence of low (10 mumol/L) zidovudine concentrations. Enzyme activity of the nuclear-encoded mitochondrial citrate synthase was not affected, and the partially mitochondrial-encoded cytochrome c oxidase was not decreased, except only after exposure to high concentrations (5 mmol/L) zidovudine. No decrease of mtDNA content and no mtDNA deletions were found in zidovudine-exposed muscle cells. We propose that the effect of zidovudine on muscle, seen in zidovudine-treated AIDS patients, results mainly from decrease in proliferation of muscle cells rather than inhibition of mtDNA replication.
Herzberg
N H
NH
Department of Neurology, Academical Medical Center, Amsterdam, The Netherlands.
Zorn
I
I
Zwart
R
R
Portegies
P
P
Bolhuis
P A
PA
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000201:enzymology; D009132:Muscles / Q000166:cytology / Q000187:drug effects*; D009135:Muscular Diseases / Q000139:chemically induced; D015215:Zidovudine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D004272:DNA, Mitochondrial; D015215:Zidovudine; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D003402:Creatine Kinase