Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines.
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5391095?pdf=render |
| _version_ | 1811319731462864896 |
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| author | Amit P Bhavsar Erandika P Gunaretnam Yuling Li Jafar S Hasbullah Bruce C Carleton Colin J D Ross |
| author_facet | Amit P Bhavsar Erandika P Gunaretnam Yuling Li Jafar S Hasbullah Bruce C Carleton Colin J D Ross |
| author_sort | Amit P Bhavsar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T12:47:47Z |
| format | Article |
| id | doaj.art-d66374bca20f40f48dd5062b0d700186 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T12:47:47Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-d66374bca20f40f48dd5062b0d7001862022-12-22T02:46:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01124e017571110.1371/journal.pone.0175711Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines.Amit P BhavsarErandika P GunaretnamYuling LiJafar S HasbullahBruce C CarletonColin J D RossCisplatin 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.http://europepmc.org/articles/PMC5391095?pdf=render |
| spellingShingle | Amit P Bhavsar Erandika P Gunaretnam Yuling Li Jafar S Hasbullah Bruce C Carleton Colin J D Ross Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. PLoS ONE |
| title | Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. |
| title_full | Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. |
| title_fullStr | Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. |
| title_full_unstemmed | Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. |
| title_short | Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines. |
| title_sort | pharmacogenetic variants in tpmt alter cellular responses to cisplatin in inner ear cell lines |
| url | http://europepmc.org/articles/PMC5391095?pdf=render |
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