Open AccessCytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People
Author(s) -
Khan Burhan A.,
Robinson Renee,
Fohner Alison E.,
Muzquiz LeeAnna I.,
Schilling Brian D.,
Beans Julie A.,
Olnes Matthew J.,
Trawicki Laura,
Frydenlund Holly,
Laukes Cindi,
Beatty Patrick,
Phillips Brian,
Nickerson Deborah,
Howlett Kevin,
Dillard Denise A.,
Thornton Timothy A.,
Thummel Kenneth E.,
Woodahl Erica L.
Publication year - 2018
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12542
Subject(s) - cyp2d6 , tamoxifen , cytochrome p450 , pharmacogenetics , cyp2c9 , biology , cyp3a4 , pharmacology , cyp2c19 , population , genetic variation , cyp3a5 , medicine , breast cancer , oncology , genetics , gene , cancer , endocrinology , genotype , metabolism , environmental health
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.