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Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.
MedLine Citation:
PMID:  20827217     Owner:  NLM     Status:  In-Data-Review    
OBJECTIVE: : Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors.
METHODS: : Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks.
RESULTS: : Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects.
CONCLUSIONS: : Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.
Kerstin Balcarek; Nils Venhoff; Catherine Deveaud; Bertrand Beauvoit; Jacques Bonnet; Janbernd Kirschner; Ana C Venhoff; Dirk Lebrecht; Ulrich A Walker
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of acquired immune deficiency syndromes (1999)     Volume:  55     ISSN:  1944-7884     ISO Abbreviation:  J. Acquir. Immune Defic. Syndr.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-09-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100892005     Medline TA:  J Acquir Immune Defic Syndr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  550-7     Citation Subset:  IM; X    
From the *Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany; †Centre of Chronic Immunodeficiency (CCI), Freiburg, Germany; ‡INSERM U828, Pessac, France; §Department of Neuropediatrics and Muscle Disorders, Medizinische Universitätsklinik, Freiburg, Germany; and ∥Department of Rheumatology, Basel University, Basel, Switzerland.
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