In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells.
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 muM RTV and 40 muM 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.
Vidal
Francesc
F
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. fvidal@comt.es
Domingo
Joan Carles
JC
Guallar
Jordi
J
Saumoy
Maria
M
Cordobilla
Begoña
B
Sánchez de la Rosa
Rainel
R
Giralt
Marta
M
Alvarez
Maria Luisa
ML
López-Dupla
Miguel
M
Torres
Ferran
F
Villarroya
Francesc
F
Cihlar
Tomas
T
Domingo
Pere
P
D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D019380:Anti-HIV Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000187:drug effects; D016049:Didanosine / Q000633:toxicity; D004347:Drug Interactions; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects*; D061466:Lopinavir; D008928:Mitochondria / Q000187:drug effects*; D063065:Organophosphonates / Q000633:toxicity*; D011744:Pyrimidinones / Q000633:toxicity; D012313:RNA / Q000096:biosynthesis; D019438:Ritonavir / Q000633:toxicity; D000068698:Tenofovir; D015215:Zidovudine / Q000633:toxicity
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D011744:Pyrimidinones; D061466:Lopinavir; D015215:Zidovudine; D012313:RNA; D000068698:Tenofovir; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D000225:Adenine; D016049:Didanosine; D019438:Ritonavir