Uridine supplementation antagonizes zidovudine-induced mitochondrial myopathy and hyperlactatemia in mice.

Abstract

OBJECTIVE:

Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.

METHODS:

BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.

RESULTS:

Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA-encoded cytochrome c oxidase I subunit, but not of nucleus-encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.

CONCLUSION:

Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.

• Authors: Dirk Lebrecht, Catherine Deveaud, Bertrand Beauvoit, Jacques Bonnet, Janbernd Kirschner, Ulrich A Walker
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 58 Issue 1 Pg. 318-26 (Jan 2008) ISSN: 0004-3591 [Print] United States
• PMID: 18163507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Lactates
• Reverse Transcriptase Inhibitors
• Triglycerides
• Zidovudine
• Malondialdehyde
• Zalcitabine
• Electron Transport Complex IV
• Uridine

Topics

• Animals
• DNA, Mitochondrial (metabolism)
• Drug Interactions
• Electron Transport (drug effects)
• Electron Transport Complex IV (metabolism)
• Gene Dosage
• Lactates (blood)
• Lipid Peroxidation (drug effects)
• Male
• Malondialdehyde (metabolism)
• Mice
• Mice, Inbred BALB C
• Mitochondrial Myopathies (chemically induced, pathology, prevention & control)
• Muscle, Skeletal (pathology)
• Reverse Transcriptase Inhibitors (toxicity)
• Triglycerides (metabolism)
• Uridine (pharmacology)
• Zalcitabine (toxicity)
• Zidovudine (toxicity)