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Uridine In Vitro Improves Mitochondrial Effect of Nukes
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Reported by Jules Levin
IAS-Rio July 2005
"Uridine prevents and treats the lipoatrophic phenotype of adipocytes exposed to stavudine, zalcitabine and zidovudine"
Walker U.A.1, Auclair M.2, Lebrecht D.1, Kornprobst M.2, Capeau J.2, Caron M.2
1Medizinische Universit酹sklinik, Dept. of Rheumatology & Clin. Immunology, Freiburg, Germany, 2INSERM U402, Faculty of Medicine Saint-Antoine,
Paris, France
Introduction: NRTI side effects have been attributed to mitochondrial toxicity. Beneficial effects of the pyrimidine precursor uridine on NRTI-induced
mitochondrial damage have been described in hepatocytes. We assessed whether uridine can abrogate the adverse effect of stavudine and zalcitabine
on adipocyte functions.
Methods: 3T3-F442A preadipocytes were exposed to zidovudine (1然), stavudine (10 然) or zalcitabine (0.2 然) in the absence or presence of
different concentrations of uridine (10-200 然) for 21 days before, and 7 days after induction of differentiation. Lipid accumulation (oil red staining),
apoptosis (flow cytometry), mitochondrial DNA (mtDNA) levels, and mitochondrial membrane potential (JC-1 aggregate/monomer ratio) were evaluated
at day 7 of differentiation.
Results:
Prolonged treatment with all NRTIs markedly altered adipose cell morphology.
Adipocytes were enlarged and contained lipid droplets of reduced size and number.
Stavudine and zalcitabine significantly decreased lipid accumulation (by 36 and 20%, respectively) and increased apoptosis. Stavudine and zalcitabine markedly decreased adipocyte mtDNA to residual amounts of 36% (p=0.006) and 45% (p=0.01). Both NRTIs also induced mitochondrial depolarization.
The effects were dose-dependent (p<0.001) and significant with uridine concentrations equal or above 50 然. Uridine had no intrinsic effects on the adipocyte phenotype, but abrogated the adverse effects of both NRTIs on adipocyte morphology and lipid content. Uridine normalized apoptotic indices & lipid loss in adipocytes exposed to d4T, AZT & ddC, prevented mtDNA-depletion by stavudine and zalcitabine and normalized mitochondrial respiration (JC-1). Uridine also normalized adipocyte dysfunction related to zidovudine exposure. Uridine (200uM) prevented the loss of intracellular lipid droplets in adipocytes surviving d4T, AZT, & ddC exposure (oil red stain).
Conclusions: Uridine supplementation protects cultured adipocytes from the adverse effects of pyrimidine analogues on lipid accumulation, cell survival
and mitochondrial functions. The beneficial effect of uridine suggests that the toxic effects of these NRTIs could be linked to an intracellular depletion of
uridine or its metabolites. Uridine supplementation could allow competition of uridine metabolites with NRTIs at polymerase-gamma and thus prevent
mtDNA-depletion. PK studies with the dietary supplement Mitocnol (NucleomaxX) show that uridine can be effectively substituted in humans.. Uridine is an interesting 'candidate' in the prevention and treatment of lipoatrophy in vivo.
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