Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites

Abstract

Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in interindividual differences in TAM metabolism, cell lines overexpressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extrahepatic UGTs, the UGT1A8 173Ala/277Tyr variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. Little or no difference in TAM glucuronidating activity was observed for the UGT1A8 173Gly/277Cys or UGT1A10 139Lys variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7 268Tyr variant exhibited significant (P < 0.01) 2-and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, compared with wild-type UGT2B7 268His. In studies of 111 human liver microsomal specimens, the rate of Oglucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (P < 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr 268 Tyr genotype compared with subjects with the UGT2B7 His 268 His genotype, with a significant (P < 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7 268His allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in interindividual variability in TAM metabolism and response to TAM therapy.

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

“…Although the effects of functional UGT polymorphisms on the glucuronidation of Tam were the focus of previous research (Sun et al, 2006;Blevins-Primeau et al, 2009;Lazarus et al, 2009;Lazarus and Sun, 2010), to our knowledge, this study is the first to describe the association of UGT1A4 promoter SNPs and glucuronidation of N-Tam, N-4OHTam, O-4OHTam N-Tor, N-4OHTor, and O-4OHTor. Here we demonstrated a significant impact of genetic variability in the UGT1A4 promoter region on xenobiotic glucuronidation, which highlights the importance of UGT1A4 genotype in breast cancer pharmacogenomic studies.…”

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…For example, UDP-glucuronosyl-transferase (UGT) 2B subfamily enzymes (UGT2B7, UGT2B11, UGT2B28) catalyzes conjugation glucuronic acid and facilitate elimination of potentially toxic compounds, particularly steroids, from target cells. UGT2B7 has unique specificity for 3,4-catechol estrogens and estriol, and may protect breast tissues from carcinogenic estrogen metabolites locally (43,44). Expression of UGT2B7 and 2B11 genes was found to be decreased in breast cancer and in benign biopsies from healthy women with high mammographic density, a strong breast cancer risk factor (45).…”

UGT2B Gene Expression Analysis in Multiple Tobacco Carcinogen-Targeted Tissues

“…A UGT2B7 codon 268 singlenucleotide polymorphism resulting in a His . Tyr amino acid change was associated with functional differences in UGT2B7 activity against NNAL (Wiener et al, 2004b) and other substrates (Blevins-Primeau et al, 2009). Studies are required to examine the role of this and other functional UGT2B7 variants in pancreatic cancer susceptibility.…”