Walker UA, Koch E, Venhoff N, Schneider J, Setzer B; IAS Conference on HIV Pathogenesis and Treatment (2nd : 2003 : Paris, France).
Antivir Ther. 2003; 8 (Suppl.1): abstract no. 745.
Dpt. of Clinical Immunology
PURPOSE: To evaluate if uridine may be suitable to prevent and treat NRTI-related mitochondrial toxicity. METHODS: Human HepG2-hepa-tocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and a mtDNA-encoded respiratory chain subunit (COX II) were measured. Phenotypic HIV-resistance assays were performed with T cell and macrophage-tropic HIV-strains. RESULTS: HepG2 cells exposed to ddC (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA-levels) and of COX II with profoundly increased cell death, lactic acid (350%) and intracellular steatosis. Uridine fully prevented cell death in the presence of ddC. Uridine fully normalized lactate and intracellular lipids by adjusting mtDNA-levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent and maximal at 200 micro-M of uridine. Uridine also rapidly and fully restored cell function when added to cells dysplaying severe mitochondrial dysfunction (ddC for 15 days) despite continued NRTI-exposure. Similar results were found in HepG2 cells exposed to d4T (a pyrimidine analogue), but not with ddI (a purine). Further experiments suggest that the mechanism involves efficient competition of uridine with NRTI-pyrimidines at gamma-polymerase, but not at HIV-reverse transcriptase. Uridine also protected HepG2-mitochondria from AZT (7 micro-M) +3TC (8 micro-M), albeit this mechanism is unclear. Pharmacokinetic studies in humans with mitocnol a new dietary supplement aimed at improving uridine levels are pending. CONCLUSIONS: Uridine supplementation may be an antiretrovirally safe strategy to prevent and treat toxicity by NRTI-pyrimidines and should be evaluated in humans.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Antimetabolites
- DNA, Mitochondrial
- Didanosine
- HIV Infections
- Humans
- Lamivudine
- Mitochondria
- Stavudine
- Uridine
- Zalcitabine
Other ID:
UI: 102263024
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