A Potential Role for Human UDP-Glucuronosyltransferase 1A4 Promoter Single Nucleotide Polymorphisms in the Pharmacogenomics of Tamoxifen and Its Derivatives

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 cytochrome P450-mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives , toremifene (Tor), and 4-hydroxytoremifene (4OHTor)] was examined using recombinant human UDP-glucuronosyltransferases (UGTs) from the 1A subfamily and human hepatic microsomes. Recombinant UGT1A4 catalyzed the formation of N-glucuronides of Tam and its derivatives and was the most active UGT enzyme toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter region of UGT1A4 have the ability to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro activity of 64 genotyped human liver microsomes was used to determine the association between the UGT1A4 promoter and coding region SNPs and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for 2163G/A and 2217T/G. These alterations in glucuronidation may lead to prolonged circulating half-lives and may potentially modify the effectiveness of these drugs in the treatment of breast cancer.

Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients

“…These data suggest that the UGT1A4 Leu48Val polymorphism could be correlated with significantly reduced glucuronidation levels of active hydroxylated TAM metabolites, and has been attributed similar effects on substrates such as naphthylamine or dihydrotestosterone [ 18 ]. Similar findings have been recently reported for 4-OH-TAM in microsomes in the case of other SNPs affecting the UGT1A4 promotor region [ 35 ]. Modified glucuronidation could affect half-lives of circulating TAM metabolites and this could alter the effectiveness of these drugs for the treatment of breast cancer.…”

Guest Editorial: Breast Cancer Epigenetics in the Era of Precision Medicine

“…Recent advances in the field of breast cancer pharmacogenomics provide strong evidence that acquired or inherited genetic differences in drug metabolic pathways can affect an individual's response to TAM and other chemotherapeutic drugs [7][8][9][10]. In support of these observations, our pharmacogenetic study showed that a single nucleotide polymorphism in the promoter of the TAM metabolizing gene UDP-glucuronosyltransferase 1A4 (UGT1A4) significantly decreases how TAM and its derivatives are metabolized in the human liver [11]. These studies, along with countless other pharmacogenomic studies, demonstrate the influence of pharmacogenomics on policy implementation and efforts that guide the development of more effective medical treatments tailored to an individual's genetic makeup.…”

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine

“…The discrepancies between all these studies including the present one may have several causes; the most likely being methodological issues and uncontrolled variables, e.g. factors that modulate gene expression: not only is there a plethora of known polymorphisms in the gene encoding the UGT1A4 enzyme itself (most of them not investigated for potential clinical effects, and not controlled for in the present and in previous studies), but a large number of SNPs in the UGT1A4 promoter region have also been identified and found to change UGT1A4 enzymatic activity; their allele frequency may reach up to as high as 44 % (Benoit-Biancamano et al 2009;Edavana et al 2013;Greer et al 2014). Moreover, other epigenetic factors may affect UGT1A4 enzyme expression: various ligand-activated and tissue-specific transcription factors like the aryl hydrocarbon receptor and hepatocyte nuclear factor 1a have been suggested to play a role (Kiang et al 2005;Rowland et al 2013).…”