ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia
| Autor: | R. M. Baldwin, Federico Innocenti, Jacqueline Ramírez, Megan Li, Deanna L. Kroetz, Mark J. Ratain, Eric L. Seiser |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Transcriptional Activation 0301 basic medicine Neutropenia Genotype ATP-binding cassette transporter Pharmacology Biology Irinotecan Polymorphism Single Nucleotide Article 03 medical and health sciences 0302 clinical medicine Genetic variation Genetics medicine Humans Aged Membrane Transport Proteins Middle Aged medicine.disease Neoplasm Proteins 030104 developmental biology Genetic marker 030220 oncology & carcinogenesis Absolute neutrophil count ABCC1 biology.protein Molecular Medicine ATP-Binding Cassette Transporters Female Efflux medicine.drug |
| Zdroj: | The Pharmacogenomics Journal. 18:35-42 |
| ISSN: | 1473-1150 1470-269X |
| Popis: | Neutropenia is a common dose-limiting toxicity associated with irinotecan treatment. Although UGT1A1 variants have been associated with neutropenia, a fraction of neutropenia risk remains unaccounted for. To identify additional genetic markers contributing to variability in irinotecan pharmacokinetics and neutropenia, a regression analysis was performed in 78 irinotecan-treated patients to analyze comprehensively three hepatic efflux transporter genes (ABCB1, ABCC1 and ABCG2). rs6498588 (ABCC1) and rs12720066 (ABCB1) were associated with increased SN-38 exposure, and rs17501331 (ABCC1) and rs12720066 were associated with lower absolute neutrophil count nadir. rs6498588 and a variant in high linkage disequilibrium are located in transcriptionally active regions or are predicted to alter transcription factor binding sites. While enhancer activity was not evident in vitro for genomic regions containing these single-nucleotide polymorphisms, rs6498588 was significantly associated with ABCC1 expression in human liver. These results suggest that genetic variation in ABCC1 and ABCB1 may contribute to irinotecan-induced neutropenia by altering expression of transporters involved in irinotecan metabolite disposition. |
| Databáze: | OpenAIRE |
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