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A potential role for human UDP‐glucuronosyltransferase 1A4 promoter SNPs in the pharmacogenomics of Tamoxifen and its derivatives (1141.13)
Author(s) -
Dates Centdrika,
Greer Aleksandra,
Bratton Stacie,
Koroth Edavana Vineetha,
Kadlubar Susan,
RadominskaPandya Anna
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1141.13
Subject(s) - glucuronidation , toremifene , glucuronosyltransferase , microsome , tamoxifen , single nucleotide polymorphism , cyp2d6 , pharmacology , chemistry , biology , cytochrome p450 , enzyme , biochemistry , cancer , breast cancer , gene , genetics , genotype
Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly N‐glucuronidated via the tertiary amine group or O‐glucuronidated after cytochromes P450 mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives [4OHTamoxifen (4OHTam), Toremifene (Tor), and 4OHTor] has been studied using recombinant human UGTs from the 1A family and human hepatic microsomes (HLM). Recombinant UGT1A4 was found to catalyze the formation of N‐ glucuronides of Tam and its derivatives and to be the most active UGT isoform toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter of UGT1A4 have the potential to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro assays using 64 genotyped HLM were used to determine the association between UGT1A4 promoter and coding region polymorphisms and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for ‐163G