Zidovudine Induces Visceral Mitochondrial Toxicity and Intra-Abdominal Fat Gain in a Rodent Model of Lipodystrophy

Carr A. , Cooper D.A. Adverse effects of antiretroviral therapy. Lancet 2000; 356: 1423–1430.

Nolan D. , Hammond E. , James I. , McKinnon E. , Mallal S. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther 2003; 8: 617–626.

Nolan D. , Hammond E. , Martin A. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003; 17: 1329–1338.

Alam N. , Cortina-Borja M. , Goetghebuer T. Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors. J Acquir Immune Defic Syndr 2012; 59: 314–324.

Carr A. , Samaras K. , Chisholm D.J. , Cooper D.A. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–1883.

Kakuda T.N. , Brundage R.C. , Anderson P.L. , Fletcher C.V. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS 1999; 13: 2311–2312.

Kakuda T.N. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22: 685–708.

Caron M. , Auclair M. , Lagathu C. The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 2004; 18: 2127–2136.

Gattermann N. , Dadak M. , Hofhaus G. Severe impairment of nucleotide synthesis through inhibition of mitochondrial respiration. Nucleosides Nucleotides Nucleic Acids 2004; 23: 1275–1279.

Walker U.A. , Auclair M. , Lebrecht D. , Kornprobst M. , Capeau J. , Caron M. Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Antivir Ther 2006; 11: 25–34.

Setzer B. , Lebrecht D. , Walker U.A. Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine. Am J Pathol 2008; 172: 681–690.

McGee K.C. , Shahmanesh M. , Boothby M. Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones. Antivir Ther 2012; 17: 495–507.

Mauss S. , Berger F. , Carls H. , Schmutz G. Rapid development of central adiposity after postexposure prophylaxis with antiretroviral drugs: a proof of principle? AIDS 2003; 17: 944–945.

van Vonderen M.G.A. , van Agtmael M.A. , Hassink E.A.M. Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss. PLoS ONE 2009; 4: e5647.

Boothby M. , McGee K.C. , Tomlinson J.W. Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months. Antivir Ther 2009; 14: 1089–1100.

Feeney E.R. , van Vonderen M.G.A. , Wit F. Zidovudine/ lamivudine but not nevirapine in combination with lopinavir/ritonavir decreases subcutaneous adipose tissue mitochondrial DNA. AIDS 2012; 26: 2165–2174.

Venhoff N. , Zilly M. , Lebrecht D. Uridine pharmacokinetics of mitocnol, a sugar cane extract. AIDS 2005; 19: 739–740.

Weinberg M.E. , Roman M.C. , Jacob P. Enhanced uridine bioavailability following administration of a triacetyluridine-rich nutritional supplement. PLoS ONE 2011; 6: e14709.

Collins M.L. , Sondel N. , Cesar D. , Hellerstein M.K. Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans. J Acquir Immune Defic Syndr 2004; 37: 1132–1139.

Lebrecht D. , Setzer B. , Ketelsen U-P , Haberstroh J. , Walker U.A. Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 2003; 108: 2423–2429.

Walker U.A. , Setzer B. , Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS 2002; 16: 2165–2173.

Schon E.A. , Rizzuto R. , Moraes C.T. , Nakase H. , Zeviani M. , DiMauro S. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science 1989; 244: 346–349.

Samuels D.C. , Schon E.A. , Chinnery P.F. Two direct repeats cause most human mtDNA deletions. Trends Genet 2004; 20: 393–398.

Edris W. , Burgett B. , Stine O.C. , Filburn C.R. Detection and quantitation by competitive PCR of an age-associated increase in a 4.8-kb deletion in rat mitochondrial DNA. Mutat Res 1994; 316: 69–78.

Lebrecht D. , Kokkori A. , Ketelsen U P. Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. J Pathol 2005; 207: 436–444.

King M P. . Use of ethidium bromide to manipulate ratio of mutated and wild-type mitochondrial DNA in cultured cells. Methods Enzymol 1996; 264: 339–344.

Walker U.A. , Bickel M. , Lütke Volksbeck S.I. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002; 29: 117–121.

Hammond E. , Nolan D. , James I. , Metcalf C. , Mallal S. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 2004; 18: 815–817.

De Pauw A. , Tejerina S. , Raes M. , Keijer J. , Arnould T. Mitochondrial (Dys)function in Adipocyte (De) differentiation and Systemic Metabolic Alterations. Am J Pathol 2009; 175: 927–939.

Lafontan M. , Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 2003; 24: 276–283.

Deveaud C. , Beauvoit B. , Hagry S. Site specific alterations of adipose tissue mitochondria in 3′-azido-3-'deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy? Biochem Pharmacol 2005; 70: 90–101.

Deveaud C. , Beauvoit B. , Salin B. , Schaeffer J. , Rigoulet M. Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes. Mol Cell Biochem 2004; 267: 157–166.

Benbrik E. , Chariot P. , Bonavaud S. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci 1997; 149: 19–25.

Stadhouders A.M. , Sengers R.C. Morphological observations in skeletal muscle from patients with a mitochondrial myopathy. J Inherit Metab Dis 1987; 10 Suppl 1: 62–80.

Corral-Debrinski M. , Stepien G. , Shoffner J.M. Hypoxemia is associated with mitochondrial DNA damage and gene induction. JAMA 1991; 266: 1812–1816.

Mazat J.P. , Rossignol R. , Malgat M. , Rocher C. , Faustin B. , Letellier T. What do mitochondrial diseases teach us about normal mitochondrial functions…that we already knew: threshold expression of mitochondrial defects. Biochim Biophys Acta 2001; 1504: 20–30.

Lenaz G. , Baracca A. , Carelli V. , D'Aurelio M. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta 2004; 1658: 89–94.

Song S. , Pursell Z.F. , Copeland W.C. , Longley M.J. , Kunkel T.A. , Mathews C.K. DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci U S A 2005; 102: 4990–4995.

Song S. , Wheeler L.J. , Mathews C.K. Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA. J Biol Chem 2003; 278: 43893–43896.

Giusti V. , Suter M. , Verdumo C. , Gaillard R.C. , Burckhardt P. , Pralong F.P. Molecular determinants of human adipose tissue: differences between visceral and subcutaneous compartments in obese women. J Clin Endocrinol Metab 2004; 89: 1379–1384.

Barile M. , Valenti D. , Quagliariello E. , Passarella S. Mitochondria as cell targets of AZT (zidovudine). Gen Pharmacol 1998; 31: 531–538.

Deveaud C. , Beauvoit B. , Reynaud A. , Bonnet J. Site-specific reduction of oxidative and lipid metabolism in adipose tissue of 3′-azido-3-'deoxythymidine-treated rats. Antimicrob Agents Chemother 2007; 51: 583–590.

Lynx M.D. , McKee E.E. 3′-Azido-3-'deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria. Biochem Pharmacol 2006; 72: 239–243.

Susan-Resiga D. , Bentley A.T. , Lynx M.D. , LaClair D.D. , McKee E.E. Zidovudine inhibits thymidine phosphorylation in the isolated perfused rat heart. Antimicrob Agents Chemother 2007; 51: 1142–1149.

Sutinen J. , Walker U.A. , Sevastianova K. Uridine supplementation for the treatment of antiretroviral therapy-associated lipoatrophy: a randomized, double-blind, placebo-controlled trial. Antivir Ther 2007; 12: 97–105.

McComsey G.A. , Walker U.A. , Budhathoki C.B. Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229. AIDS 2010; 24: 2507–2515.