| First Author | Bhavsar AP | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 4 | Pages | e0175711 |
| PubMed ID | 28406961 | Mgi Jnum | J:245150 |
| Mgi Id | MGI:5915578 | Doi | 10.1371/journal.pone.0175711 |
| Citation | Bhavsar AP, et al. (2017) Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. PLoS One 12(4):e0175711 |
| abstractText | Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant. The expression of wild type TPMT (TPMT*1) in two murine ear cell lines, HEI-OC1 and UB/OC-1, significantly mitigated their susceptibility to cisplatin toxicity. Cisplatin treatment induced Tlr4 gene expression in HEI-OC1 cells and this response was blunted by the expression of wild type TPMT but not TPMT*3A. In line with the significant mitigation of TPMT*1-expressing cells to cisplatin cytotoxicity, these findings demonstrate a drug-gene interaction between increased TPMT activity and decreased susceptibility to cisplatin-induced toxicity of inner ear cells. |
