Open AccessThe NRTI BMS‐986001 does not degrade mitochondrial DNA in long‐term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat
Author(s) -
Wang F,
Flint O
Publication year - 2012
Publication title -
journal of the international aids society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.724
H-Index - 62
ISSN - 1758-2652
DOI - 10.7448/ias.15.6.18316
Subject(s) - cytotoxic t cell , mitochondrial toxicity , medicine , reverse transcriptase inhibitor , pharmacology , abacavir , stavudine , in vitro , zidovudine , in vivo , virology , toxicity , microbiology and biotechnology , biology , biochemistry , virus , viral load , antiretroviral therapy , viral disease
Background Nucleoside reverse transcriptase inhibitors (NRTIs) are often used in the treatment of HIV infections, although their use has been in some cases been limited by adverse side effects attributed to inhibition of eukaryotic mitochondrial DNA polymerase gamma (mtDNA polγ). The primary objective of this study was to compare the in vitro toxicity of the novel HIV thymidine‐analogue NRTI, BMS‐986001 (OBP‐601) to that of five other NRTIs: tenofovir (TFV), adefovir (ADV), azidothymidine (AZT), stavudine (D4T), and abacavir (ABC). Methods Primary cultures of human renal proximal tubule epithelium, muscle, preadipocytes and differentiated adipocytes (subcutaneous) were exposed to each of the NRTIs at their reported C max concentration and at 200 M for 5, 10, 14 and 19 days. Six in vitro cytotoxicity parameters were measured: percent dead cells, cell protein and ATP content, lactate concentration in the media, and mtDNA (ATP8) content by qPCR. Results were analyzed by analysis of variance followed by Dunnet's post hoc test. Results BMS‐986001 was not cytotoxic in any of the 4 cell culture systems tested. TFV was cytotoxic in muscle cells and preadipocytes with regard to mtDNA content which decreased in a concentration‐ and time‐dependent manner to approximately 40% control values. In contrast, ADV, AZT and d4T were cytotoxic in all 4 cell culture systems and with regard to all measured parameters. ABC was only significantly cytotoxic at the higher concentration (200 M) tested. Conclusions Based on in vitro assessments, when compared to five other NRTIs (TFV, ADV, AZT, d4T and ABC) in primary cultures of human cells, BMS‐986001 was the least cytotoxic. The most cytotoxic were ADV, AZT, and d4T. In spite of their very close structural similarity, the relative lack of toxicity of BMS‐986001 compared to d4T is consistent with the 100‐fold greater potency of d4T for inhibition of mtDNA polγ.