This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Birkus, G.
Right arrow Articles by Cihlar, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Birkus, G.
Right arrow Articles by Cihlar, T.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, March 2002, p. 716-723, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.716-723.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Gabriel Birkus, Michael J. M. Hitchcock, and Tomas Cihlar*

Gilead Sciences, Foster City, California 94404

Received 17 July 2001/ Returned for modification 22 October 2001/ Accepted 3 December 2001

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 µM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 µM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 µM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 µM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 µM) is not associated with mitochondrial toxicity.

* Corresponding author. Mailing address: Gilead Sciences, 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5637. Fax: (650) 522-5890. E-mail: tomas_cihlar{at}gilead.com.

Antimicrobial Agents and Chemotherapy, March 2002, p. 716-723, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.716-723.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Maagaard, A., Kvale, D. (2009). Mitochondrial toxicity in HIV-infected patients both off and on antiretroviral treatment: a continuum or distinct underlying mechanisms?. J Antimicrob Chemother 64: 901-909 [Abstract] [Full Text]  
  • Gerschenson, M., Kim, C., Berzins, B., Taiwo, B., Libutti, D. E., Choi, J., Chen, D., Weinstein, J., Shore, J., da Silva, B., Belsey, E., McComsey, G. A., Murphy, R. L. (2009). Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen. J Antimicrob Chemother 63: 1244-1250 [Abstract] [Full Text]  
  • Saitoh, A., Haas, R. H., Naviaux, R. K., Salva, N. G., Wong, J. K., Spector, S. A. (2008). Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial DNA and RNA in Human Skeletal Muscle Cells. Antimicrob. Agents Chemother. 52: 2825-2830 [Abstract] [Full Text]  
  • Bridges, E. G., Selden, J. R., Luo, S. (2008). Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis B. Antimicrob. Agents Chemother. 52: 2521-2528 [Abstract] [Full Text]  
  • Wierzbicki, A. S, Purdon, S. D, Hardman, T. C, Kulasegaram, R., Peters, B. S (2008). Review: Clinical aspects of the management of HIV lipodystrophy. British Journal of Diabetes & Vascular Disease 8: 113-119 [Abstract]  
  • Cihlar, T., Ray, A. S., Boojamra, C. G., Zhang, L., Hui, H., Laflamme, G., Vela, J. E., Grant, D., Chen, J., Myrick, F., White, K. L., Gao, Y., Lin, K.-Y., Douglas, J. L., Parkin, N. T., Carey, A., Pakdaman, R., Mackman, R. L. (2008). Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131. Antimicrob. Agents Chemother. 52: 655-665 [Abstract] [Full Text]  
  • Mazzucco, C. E., Hamatake, R. K., Colonno, R. J., Tenney, D. J. (2008). Entecavir for Treatment of Hepatitis B Virus Displays No In Vitro Mitochondrial Toxicity or DNA Polymerase Gamma Inhibition. Antimicrob. Agents Chemother. 52: 598-605 [Abstract] [Full Text]  
  • Saitoh, A., Fenton, T., Alvero, C., Fletcher, C. V., Spector, S. A. (2007). Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondria in Human Immunodeficiency Virus Type 1-Infected Children Receiving Highly Active Antiretroviral Therapy. Antimicrob. Agents Chemother. 51: 4236-4242 [Abstract] [Full Text]  
  • Hanes, J. W., Zhu, Y., Parris, D. S., Johnson, K. A. (2007). Enzymatic Therapeutic Index of Acyclovir: VIRAL VERSUS HUMAN POLYMERASE {gamma} SPECIFICITY. J. Biol. Chem. 282: 25159-25167 [Abstract] [Full Text]  
  • Lund, K. C., Peterson, L. L., Wallace, K. B. (2007). Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs. Antimicrob. Agents Chemother. 51: 2531-2539 [Abstract] [Full Text]  
  • Vidal, F., Domingo, J. C., Guallar, J., Saumoy, M., Cordobilla, B., Sanchez de la Rosa, R., Giralt, M., Alvarez, M. L., Lopez-Dupla, M., Torres, F., Villarroya, F., Cihlar, T., Domingo, P. (2006). In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells. Antimicrob. Agents Chemother. 50: 3824-3832 [Abstract] [Full Text]  
  • Ray, A. S., Cihlar, T., Robinson, K. L., Tong, L., Vela, J. E., Fuller, M. D., Wieman, L. M., Eisenberg, E. J., Rhodes, G. R. (2006). Mechanism of active renal tubular efflux of tenofovir.. Antimicrob. Agents Chemother. 50: 3297-3304 [Abstract] [Full Text]  
  • Pruvost, A., Negredo, E., Benech, H., Theodoro, F., Puig, J., Grau, E., Garcia, E., Molto, J., Grassi, J., Clotet, B. (2005). Measurement of Intracellular Didanosine and Tenofovir Phosphorylated Metabolites and Possible Interaction of the Two Drugs in Human Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemother. 49: 1907-1914 [Abstract] [Full Text]  
  • Ray, A. S., Hernandez-Santiago, B. I., Mathew, J. S., Murakami, E., Bozeman, C., Xie, M.-Y., Dutschman, G. E., Gullen, E., Yang, Z., Hurwitz, S., Cheng, Y.-C., Chu, C. K., McClure, H., Schinazi, R. F., Anderson, K. S. (2005). Mechanism of Anti-Human Immunodeficiency Virus Activity of {beta}-D-6-Cyclopropylamino-2',3'-Didehydro-2',3'-Dideoxyguanosine. Antimicrob. Agents Chemother. 49: 1994-2001 [Abstract] [Full Text]  
  • Yarasheski, K. E., Smith, S. R., Powderly, W. G. (2005). Reducing plasma HIV RNA improves muscle amino acid metabolism. Am. J. Physiol. Endocrinol. Metab. 288: E278-E284 [Abstract] [Full Text]  
  • Anderson, P. L (2004). Pharmacologic Perspectives for Once-Daily Antiretroviral Therapy. The Annals of Pharmacotherapy 38: 1924-1934 [Abstract] [Full Text]  
  • Gallant, J. E., Staszewski, S., Pozniak, A. L., DeJesus, E., Suleiman, J. M. A. H., Miller, M. D., Coakley, D. F., Lu, B., Toole, J. J., Cheng, A. K., for the 903 Study Group, (2004). Efficacy and Safety of Tenofovir DF vs Stavudine in Combination Therapy in Antiretroviral-Naive Patients: A 3-Year Randomized Trial. JAMA 292: 191-201 [Abstract] [Full Text]  
  • Van Rompay, K. K. A., Brignolo, L. L., Meyer, D. J., Jerome, C., Tarara, R., Spinner, A., Hamilton, M., Hirst, L. L., Bennett, D. R., Canfield, D. R., Dearman, T. G., Von Morgenland, W., Allen, P. C., Valverde, C., Castillo, A. B., Martin, R. B., Samii, V. F., Bendele, R., Desjardins, J., Marthas, M. L., Pedersen, N. C., Bischofberger, N. (2004). Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques. Antimicrob. Agents Chemother. 48: 1469-1487 [Abstract] [Full Text]  
  • Note, R., Maisonneuve, C., Letteron, P., Peytavin, G., Djouadi, F., Igoudjil, A., Guimont, M.-C., Biour, M., Pessayre, D., Fromenty, B. (2003). Mitochondrial and Metabolic Effects of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in Mice Receiving One of Five Single- and Three Dual-NRTI Treatments. Antimicrob. Agents Chemother. 47: 3384-3392 [Abstract] [Full Text]  
  • De Clercq, E. (2003). Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections. Clin. Microbiol. Rev. 16: 569-596 [Abstract] [Full Text]  
  • (2003). NRTI-Related Lactic Acidosis in an HIV-Infected Woman. AIDS Clin Care 2003: 7-7 [Full Text]  
  • Rivas, P., Polo, J., de Gorgolas, M., Fernandez-Guerrero, M. L (2003). Drug points: Fatal lactic acidosis associated with tenofovir. BMJ 327: 711-711 [Full Text]  
  • Grim, S. A, Romanelli, F. (2003). Tenofovir Disoproxil Fumarate. The Annals of Pharmacotherapy 37: 849-859 [Abstract] [Full Text]  
  • Antoniou, T., Weisdorf, T., Gough, K. (2003). Symptomatic hyperlactatemia in an HIV-positive patient: a case report and discussion. CMAJ 168: 195-198 [Abstract] [Full Text]  
  • Birkus, G., Hajek, M., Kramata, P., Votruba, I., Holy, A., Otova, B. (2002). Tenofovir Diphosphate Is a Poor Substrate and a Weak Inhibitor of Rat DNA Polymerases {alpha}, {delta}, and {varepsilon}. Antimicrob. Agents Chemother. 46: 1610-1613 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»