TUPE042 - Poster Exhibition
The HIV NRTI BMS-986001 does not degrade mitochondrial DNA in long term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat
F. Wang, O. Flint
Bristol-Myers Squibb, Discovery Toxicology, Princeton, United States
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 polg). 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 four other NRTIs: tenofovir (TDF), zidovudine (ZDV), 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 Cmax concentration and at 200 µM 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 (GAPDH DNA reference control). 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. TDF 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, ZDV 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 µM) tested.
Conclusions: Based on in vitro assessments, when compared to four other NRTIs (TDF, ZDV, d4T and ABC) in primary cultures of human cells, BMS-986001 was the least cytotoxic. The most cytotoxic were ZDV, and d4T. In spite of close structural similarity to d4T, BMS-986001 is a 75-fold more potent NRTI but a >200-fold less potent inhibitor of mtDNA polg, consistent with its lower toxicity in these human cell cultures.
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