5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

URIDINE PREVENTS AND TREATS mtDNA DEPLETION BY NRTI PYRIMIDINE ANALOGUES AND FULLY RESTORES MITOCHONDRIAL FUNCTION

Antiviral Therapy 2003; 8:L17 (abstract 19)

UA Walker¹, E Koch², N Venhoff¹, H Klinker³, P Langmann³, M Zilly³, J Schneider² and B Setzer^1
1Department of Clinical Immunology, University of Freiburg, Germany; ²Institute of Virology, University of Freiburg, Germany; and ³Department of Infectious Diseases, University of Wuerzburg, Germany

OBJECTIVE: To evaluate if uridine may be suitable to prevent and treat nucleoside reverse transcriptase inhibitor (NRTI)-related mitochondrial toxicity.

METHODS: Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the respiratory chain subunits (mtDNA-encoded: COX II, nucleus-encoded COX IV) were measured. Phenotypic HIV-resistance assays for NRTIs were performed in vitro with T cell and macrophage-tropic HIV strains in the absence of uridine and in its presence (61.5 µM, 185 µM,or 615 µM). Uridine serum levels were followed in individuals for 24 h after a single dose (36 g) of Mitocnol, a new dietary supplement.

RESULTS: HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8%) and of COX II (to 8% of wild-type levels). Zalcitabine induced a severe reduction of cell proliferation (to 20%), a severe intracellular steatosis and an increase of lactate (350% of untreated control). Uridine fully normalized cell proliferation, lactate and intracellular lipids by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. These effects were dose-dependent and maximal at 200 µM of uridine. Uridine also rapidly and fully restored cell function despite continued zalcitabine exposure, when added to cells displaying severe mitochondrial dysfunction (177 nM of zalcitabine for 15 days). Similar results were found in HepG2 cells exposed to 36 µM of stavudine (a pyrimidine analogue), but not with 11.8 µM of didanosine (a purine). Uridine also fully abrogated the increase in lactate and all the cell toxicity of zidovudine (7 µM) + lamivudine (8 µM) to HepG2 cells. All these observations were statistically significant (ANOVA). All tested concentrations of uridine did not alter the IC₅₀ or IC₉₀ of the currently licensed NRTIs in HIV resistance assays, suggesting a lack of interference with the intracellular activation, uptake or interaction with HIV reverse transcriptase. Protective uridine levels can be achieved in human serum by oral Mitocnol. Side effects were not noted.

CONCLUSIONS: Uridine fully abrogates mitochondrial toxicity by NRTI-pyrimidines in a preventive and therapeutic setting. Uridine does not appear to interfere with the antiretroviral efficacy of NRTIs. Protective levels of uridine can be achieved in humans with Mitocnol, a new dietary supplement.

Presenting author: UA Walker

2003-07-08
19

Copyright © 2003 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.