title: Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.
abstract: 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.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Balcarek
authors.forename: Nils
authors.initials: N
authors.lastname: Venhoff
authors.forename: Catherine
authors.initials: C
authors.lastname: Deveaud
authors.forename: Bertrand
authors.initials: B
authors.lastname: Beauvoit
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonnet
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Ana C
authors.initials: AC
authors.lastname: Venhoff
authors.forename: Dirk
authors.initials: D
authors.lastname: Lebrecht
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Walker
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced*; D054715:Cardiotoxins / Q000633:toxicity*; D056915:DNA Copy Number Variations / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D019587:Dietary Supplements; D003576:Electron Transport Complex IV / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000648:ultrastructure; D009154:Mutation; D009705:Nucleosides; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D014529:Uridine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016047:Zalcitabine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D054715:Cardiotoxins; D004272:DNA, Mitochondrial; D009705:Nucleosides; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D003576:Electron Transport Complex IV; D014529:Uridine