Abstract
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<A and ‐217T<G. These alterations in glucuronidation could lead to prolonged circulating half‐lives and potentially modify the effectiveness of these drugs in the treatment of breast cancer.Grant Funding Source: Supported by DoD‐W81XWH1110795 and UAMS TRI (CTSA Grant Award #UL1TR000039) ABCRP funds to AR‐P
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