Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity

CH Chen, M Vazquez-Padua and YC Cheng

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.

The anti-human immunodeficiency virus (-HIV) nucleoside analogs azidothymidine (AZT), dideoxycytidine (ddC), dideoxyinosine (ddl), dideoxydidehydrothymidine (D4T), and dideoxydidehydrocytidine (D4C) and the anticancer drug cytosine arabinoside (AraC) were compared for their effects on the mitochondrial DNA (mtDNA) content in a human lymphoblastoid cell line, CEM. The potency of these compounds in reducing mtDNA content was in the order of ddC greater than D4C greater than D4T greater than AZT greater than ddl. AraC did not have a significant effect on mtDNA content. All of the compounds tested, except AraC, stimulated lactic acid production at concentrations that inhibited mtDNA synthesis. The action of ddC and ddl occurred at concentrations that did not affect cell growth significantly in 4 days but retarded cell growth by day 6. D4T and D4C decreased mtDNA content by 50% at doses lower than those that inhibited cell growth by 50% in 4 days (ID50). However, AZT required a dose higher than the ID50 to exert similar effects on mtDNA content. The decrease of mtDNA content caused by ddC also occurred in nerve growth factor-treated PC12 cells, which differentiate to neuron-like cells upon treatment with nerve growth factor. The preferential inhibition of mtDNA, compared with cell growth, by some of these anti-HIV nucleoside analogs correlates well with their ability to cause drug-limiting delayed toxicity, such as peripheral neuropathy, in patients. These data suggest that the selective mitochondrial toxicity could be responsible for the delayed toxicity caused by these anti-HIV analogs.

Volume 39, Issue 5, pp. 625-628, 05/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				G. Yang, J. Wang, Y. Cheng, G. E. Dutschman, H. Tanaka, M. Baba, and Y.-C. Cheng Mechanism of Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by a Stavudine Analogue, 4'-Ethynyl Stavudine Triphosphate Antimicrob. Agents Chemother., June 1, 2008; 52(6): 2035 - 2042. [Abstract] [Full Text] [PDF]

				E. Paintsil, G. E. Dutschman, R. Hu, S. P. Grill, W. Lam, M. Baba, H. Tanaka, and Y.-C. Cheng Intracellular Metabolism and Persistence of the Anti-Human Immunodeficiency Virus Activity of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine, a Novel Thymidine Analog Antimicrob. Agents Chemother., November 1, 2007; 51(11): 3870 - 3879. [Abstract] [Full Text] [PDF]

				Y. Zhu, J. M. Antony, J. A. Martinez, D. M. Glerum, V. Brussee, A. Hoke, D. Zochodne, and C. Power Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression Brain, August 1, 2007; 130(8): 2011 - 2023. [Abstract] [Full Text] [PDF]

				D. M. Simpson, D. Kitch, S. R. Evans, J. C. McArthur, D. M. Asmuth, B. Cohen, K. Goodkin, M. Gerschenson, Y. So, C. M. Marra, et al. HIV neuropathy natural history cohort study: Assessment measures and risk factors Neurology, June 13, 2006; 66(11): 1679 - 1687. [Abstract] [Full Text] [PDF]

				W. Lam, C. Chen, S. Ruan, C.-H. Leung, and Y.-C. Cheng Expression of Deoxynucleotide Carrier Is Not Associated with the Mitochondrial DNA Depletion Caused by Anti-HIV Dideoxynucleoside Analogs and Mitochondrial dNTP Uptake Mol. Pharmacol., February 1, 2005; 67(2): 408 - 416. [Abstract] [Full Text] [PDF]

				L. Milazzo, M. Piazza, O. Sangaletti, N. Gatti, A. Cappelletti, F. Adorni, S. Antinori, M. Galli, M. Moroni, and A. Riva [13C]Methionine breath test: a novel method to detect antiretroviral drug-related mitochondrial toxicity J. Antimicrob. Chemother., January 1, 2005; 55(1): 84 - 89. [Abstract] [Full Text] [PDF]

				G. E. Dutschman, S. P. Grill, E. A. Gullen, K. Haraguchi, S. Takeda, H. Tanaka, M. Baba, and Y.-C. Cheng Novel 4'-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1640 - 1646. [Abstract] [Full Text] [PDF]

				J. Y. Feng, E. Murakami, S. M. Zorca, A. A. Johnson, K. A. Johnson, R. F. Schinazi, P. A. Furman, and K. S. Anderson Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2',3'-Dideoxy-5-Fluoro-3'-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1300 - 1306. [Abstract] [Full Text] [PDF]

				L D Lewis, S Amin, C I Civin, and P S Lietman Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production Human and Experimental Toxicology, April 1, 2004; 23(4): 173 - 185. [Abstract] [PDF]

				C. L. Cherry and S. L. Wesselingh Nucleoside analogues and HIV: the combined cost to mitochondria J. Antimicrob. Chemother., May 1, 2003; 51(5): 1091 - 1093. [Full Text] [PDF]

				T. Antoniou, T. Weisdorf, and K. Gough Symptomatic hyperlactatemia in an HIV-positive patient: a case report and discussion Can. Med. Assoc. J., January 21, 2003; 168(2): 195 - 198. [Abstract] [Full Text] [PDF]

				J.-Y. Liou, P. Krishnan, C.-C. Hsieh, G. E. Dutschman, and Y.-c. Cheng Assessment of the Effect of Phosphorylated Metabolites of Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Pyrimidine Analogs on the Behavior of Human Deoxycytidylate Deaminase Mol. Pharmacol., January 1, 2003; 63(1): 105 - 110. [Abstract] [Full Text] [PDF]

				D. Chen, A. Misra, and A. Garg Lipodystrophy in Human Immunodeficiency Virus-Infected Patients J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4845 - 4856. [Abstract] [Full Text] [PDF]

				P. Chariot, N. Bourokba, F. Brivet, D. A. Rastegar, J. Casademont, OÒs. Miro, F. Cardellach, J. S.G. Montaner, H. C.F. Cote, and P. R. Harrigan Mitochondrial DNA and Nucleoside Toxicity N. Engl. J. Med., July 18, 2002; 347(3): 216 - 218. [Full Text] [PDF]

				H. C.F. Cote, Z. L. Brumme, K. J.P. Craib, C. S. Alexander, B. Wynhoven, L. Ting, H. Wong, M. Harris, P. R. Harrigan, M. V. O'Shaughnessy, et al. Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV-Infected Patients N. Engl. J. Med., March 14, 2002; 346(11): 811 - 820. [Abstract] [Full Text] [PDF]

				G. Birkus, M. J. M. Hitchcock, and T. Cihlar Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors Antimicrob. Agents Chemother., March 1, 2002; 46(3): 716 - 723. [Abstract] [Full Text] [PDF]

				NRTI-Associated Mitochondrial Toxicity AIDS Clinical Care, May 1, 2001; 2001(501): 7 - 7. [Full Text]

				X.-R. Pan-Zhou, L. Cui, X.-J. Zhou, J.-P. Sommadossi, and V. M. Darley-Usmar Differential Effects of Antiretroviral Nucleoside Analogs on Mitochondrial Function in HepG2 Cells Antimicrob. Agents Chemother., March 1, 2000; 44(3): 496 - 503. [Abstract] [Full Text]

				S. G. Sarafianos, K. Das, A. D. Clark Jr., J. Ding, P. L. Boyer, S. H. Hughes, and E. Arnold Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta -branched amino acids PNAS, August 31, 1999; 96(18): 10027 - 10032. [Abstract] [Full Text] [PDF]

				J. Wang, J. Neuhard, and S. Eriksson An Escherichia coli System Expressing Human Deoxyribonucleoside Salvage Enzymes for Evaluation of Potential Antiproliferative Nucleoside Analogs Antimicrob. Agents Chemother., October 1, 1998; 42(10): 2620 - 2625. [Abstract] [Full Text]

				G. E. Dutschman, E. G. Bridges, S.-H. Liu, E. Gullen, X. Guo, M. Kukhanova, and Y.-C. Cheng Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta -D(+) Nucleoside Analogs In Vitro Antimicrob. Agents Chemother., July 1, 1998; 42(7): 1799 - 1804. [Abstract] [Full Text]

				P. Hentosh and M. Tibudan 2-Chloro-2'-deoxyadenosine, an Antileukemic Drug, Has an Early Effect on Cellular Mitochondrial Function Mol. Pharmacol., April 1, 1997; 51(4): 613 - 619. [Abstract] [Full Text]

				L. Cui, L. Locatelli, M.-Y. Xie, and J.-P. Sommadossi Effect of Nucleoside Analogs on Neurite Regeneration and Mitochondrial DNA Synthesis in PC-12 Cells J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1228 - 1234. [Abstract] [Full Text]

				R. McKenzie, M. W. Fried, R. Sallie, H. Conjeevaram, A. M. Di Bisceglie, Y. Park, B. Savarese, D. Kleiner, M. Tsokos, C. Luciano, et al. Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B N. Engl. J. Med., October 26, 1995; 333(17): 1099 - 1105. [Abstract] [Full Text] [PDF]

				S. Eriksson, B. Xu, and D. A. Clayton Efficient Incorporation of Anti-HIV Deoxynucleotides by Recombinant Yeast Mitochondrial DNA Polymerase J. Biol. Chem., August 11, 1995; 270(32): 18929 - 18934. [Abstract] [Full Text] [PDF]

				C. Zhu, M. Johansson, and A. Karlsson Incorporation of Nucleoside Analogs into Nuclear or Mitochondrial DNA Is Determined by the Intracellular Phosphorylation Site J. Biol. Chem., August 25, 2000; 275(35): 26727 - 26731. [Abstract] [Full Text] [PDF]

				J. Y. Feng, A. A. Johnson, K. A. Johnson, and K. S. Anderson Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs J. Biol. Chem., June 22, 2001; 276(26): 23832 - 23837. [Abstract] [Full Text] [PDF]

				A. A. Johnson, A. S. Ray, J. Hanes, Z. Suo, J. M. Colacino, K. S. Anderson, and K. A. Johnson Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase J. Biol. Chem., October 26, 2001; 276(44): 40847 - 40857. [Abstract] [Full Text] [PDF]