Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People

Burhan A. Khan, Renee Robinson, Alison E. Fohner, Lee Anna I. Muzquiz, Brian D. Schilling, Julie A. Beans, Matthew J. Olnes, Laura Trawicki, Holly Frydenlund, Cindi Laukes, Patrick Beatty, Brian Phillips, Deborah Nickerson, Kevin Howlett, Denise A. Dillard, Timothy A. Thornton, Kenneth E. Thummel, Erica L. Woodahl

Research output: Contribution to journalArticlepeer-review

Abstract

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4-hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

Original languageEnglish
Pages (from-to)312-321
Number of pages10
JournalClinical and Translational Science
Volume11
Issue number3
DOIs
StatePublished - May 2018

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