The effect in vitro of 2'-deoxycytidine on the metabolism and cytotoxicity of 2',3'-dideoxycytidine

Bhalla, Kapil N.; Li, Gongrong; Grant, Steven; Cole, John T.; Maclaughlin, W.; Volsky, David J.

doi:10.1097/00002030-199005000-00008

Cited by 6 publications

(2 citation statements)

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“…Oral uridine can also be administered at high doses, with mild osmotic diarrhoea being dose-limiting beyond 12 g/m 2 [27]. Due to the pharmacokinetic properties of uridine (bioavailability of 7% and serum half-life of 2 h), other sources of pyrimidine precursors, such as deoxycytidine [16,28,29], or inhibitors of uridine catabolism or excretion may be envisaged [30,31].…”

Section: Discussionmentioning

confidence: 99%

Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells

Walker¹,

Venhoff²,

Koch

et al. 2003

Antiviral Therapy

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Objective To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). 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 ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. Results HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 μM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 μM of stavudine and protected HepG2-cells exposed to 7 μM of zidovudine + 8 μM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 μM of didanosine (a purine analogue). Conclusions The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.

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Section: Discussionmentioning

confidence: 99%

Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells

Walker¹,

Venhoff²,

Koch

et al. 2003

Antiviral Therapy

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“…However, excessive oral dosing (12 g/m 2 ) is limited by mild and reversible osmotic diarrhoea due to the relatively poor bioavailability of uridine (7%) [46]. Using other pyrimidine precursors, for example, triacetyluridine [34,47,48] or inhibitors of uridine catabolism or excretion may also be envisaged [35,49,50].…”

Section: Metabolism Pharmacokinetics and Safety Of Uridine In Humansmentioning

confidence: 99%

Uridine in the Prevention and Treatment of Nrti-Related Mitochondrial Toxicity

Walker

Venhoff

2005

Antiviral Therapy

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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 NRTIs [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 μM). 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.

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