Uridine as a potential treatment for NRTI related mitochondrial toxicity
Paul Blanchard, HIV i-Base
An intriguing in vitro study was presented at the 2nd IAS Conference in Paris evaluating the potential of uridine to prevent and treat nucleoside reverse transcriptase inhibitor (NRTI) related mitochondrial toxicity. A preliminary pharmacokinetic study was also reported on an extract of sugar cane, which may be used in humans to raise plasma levels of uridine.
Human hepatocytes (HepG2) were exposed in vitro to NRTIs with or without uridine for 25 days and cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the respiratory chain subunits (mtDNA-encoded: COX II, nucleus-encoded COX IV) measured. Uridine serum levels were also followed in individuals for 24 hours after a single dose (36 grams) of Mitocnol, a new dietary supplement derived from sugar cane.
HepG2 cells exposed to 177nM of zalcitabine (ddC) without uridine developed a severe depletion of mtDNA and of COX II. ddC induced a severe reduction of cell proliferation (to 20%), a severe intracellular steatosis and an increase of lactate (350% of untreated control). Uridine fully normalised 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 200µM of uridine. Uridine also rapidly and fully restored cell function despite continued ddC exposure, when added to cells displaying severe mitochondrial dysfunction. Similar results were found in HepG2 cells exposed to stavudine (d4T) but not to didanosine (ddI). Uridine also fully abrogated the increase in lactate and all the cell toxicity of the combination of zidovudine (ZDV) and lamivudine (3TC). All tested concentrations of uridine did not alter the IC50 or IC90 of NRTIs in HIV-resistance assays, suggesting a lack of interference with the intracellular activation, uptake or interaction with HIV reverse transcriptase.
The pharmacokinetic studies revealed that protective uridine levels could be achieved in human serum by oral Mitocnol, an extract from sugar cane, rich in nucleosides. Side effects were not noted.
The researchers concluded that uridine fully abrogates mitochondrial toxicity by NRTI-pyrimidines in a preventive and therapeutic setting and does not appear to interfere with the antiretroviral efficacy of NRTIs. They went on to state that protective levels of uridine could be achieved in humans with NucleomaxXTM, a new dietary supplement containing the sugar cane extract Mitocnol.
Walker UA, Koch E, Venhoff N et al. Uridine prevents and treats mtDNA-depletion by NRTI pyrimidine analogues and fully restores mitochondrial function. 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003, Paris. Abstract 745.