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Antimicrobial Agents and Chemotherapy, November 2006, p. 3824-3832, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00437-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells{triangledown}

Francesc Vidal,1* Joan Carles Domingo,2 Jordi Guallar,2 Maria Saumoy,1 Begoña Cordobilla,2 Rainel Sánchez de la Rosa,3 Marta Giralt,2 Maria Luisa Álvarez,3 Miguel López-Dupla,1 Ferran Torres,4 Francesc Villarroya,2 Tomas Cihlar,5 and Pere Domingo6

Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain,1 Departament de Bioquimica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain,2 Gilead Sciences SL, Madrid, Spain,3 Laboratori d'Estadística i Epidemiologia, Universitat Autònoma de Barcelona, Servei de Farmacología, UASP, Hospital Clinic, Barcelona, Spain,4 Gilead Sciences, Department of Biology, Foster City, California,5 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain6

Received 6 April 2006/ Returned for modification 13 June 2006/ Accepted 11 August 2006

We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P = 0.002) and TFV (P = 0.0001). The combination of 10 µM RTV and 40 µM LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.

* Corresponding author. Mailing address: Infectious Diseases and AIDS Section, Department of Internal Medicine, Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Mallafré Guasch, 4, 43007 Tarragona, Spain. Phone: 34977295833. Fax: 34977224011. E-mail: fvidal{at}comt.es.

{triangledown} Published ahead of print on 28 August 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3824-3832, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00437-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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