Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity.
Long-term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTls [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production and intracellular steatosis. Uridine was also found to improve the liver and haematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50-200 microM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less toxic NRTIs.
Walker
Ulrich A
UA
Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany. ulrich.walker@klinikum.uni-freiburg.de
Venhoff
Nils
N
D019380:Anti-HIV Agents / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000032:analysis*; D004347:Drug Interactions; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D009705:Nucleosides / Q000009:adverse effects*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D014529:Uridine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D014529:Uridine