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- Title
Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines.
- Authors
Bhavsar, Amit P.; Gunaretnam, Erandika P.; Li, Yuling; Hasbullah, Jafar S.; Carleton, Bruce C.; Ross, Colin J. D.
- Abstract
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.
- Subjects
METHYLTRANSFERASES; CISPLATIN; PHARMACOGENOMICS; CANCER chemotherapy; CELL culture
- Publication
PLoS ONE, 2017, Vol 12, Issue 4, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0175711