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

Abstract

Tamoxifen is used to prevent and treat estrogen-dependent breast cancer. It is described as a prodrug since most of its antiestrogen effects are exerted through its hydroxylated metabolites 4-OH-tamoxifen and endoxifen. In prior work, we correlated optimal plasma levels of these metabolites with certain genotypes of CYP2D6 and SULT1A2. This descriptive study examines correlations between concentrations of tamoxifen's glucuronide metabolites and genotypes UGT1A4 Pro24Thr, UGT1A4 Leu48Val, UGT2B7 His268Tyr, UGT2B15 Asp85YTyr UGT2B15 Lys523Thr and UGT2B17del in 132 patients with estrogen receptor-positive breast cancer under treatment with tamoxifen. Patients were genotyped by real-time and conventional PCR-RFLP. The glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide were isolated from blood plasma and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Individuals who were homozygous for UGT1A448VAL showed significantly lower mean concentrations of both glucuronide metabolites compared to subjects genotyped as wt/wt plus wt/48Val (p=0.037 and p=0.031, respectively). Women homozygous for UGT2B7268Tyr also showed mean substrate/product ratios of 4-OH-tamoxifen/4-OH-tamoxifen-O-glucuronide and 4-OH-tamoxifen/4-OH-tamoxifen-N-glucuronide indicative of reduced glucuronidase activity compared to wt homozygotes or to heterozygotes for the polymorphism (p=0.005 and p=0.003, respectively). In contrast, UGT2B15 Lys523Thr and UGT2B17del were associated with possibly increased enzyme activity. Patients with at least one variant allele UGT2B15523Thr showed significantly higher 4-OH-tamoxifen-O-glucuronide and endoxifen-glucuronide levels (p=0.023 and p=0.025, respectively) indicating a variant gene-dose effect. Higher 4-OH-tamoxifen-N-glucuronide levels observed in UGT2B17del genotypes (p=0.042) could be attributed to a mechanism that compensates for the greater expression of other genes in UGT2B17 del/del individuals. Our observations suggest that patients carrying mutations UGT1A448Val, UGT2B7268Tyr or with wt genotypes for UGT2B17nodel and UGT2B15523Lys could be the best candidates for a good response to tamoxifen therapy in terms of eliciting effective plasma active tamoxifen metabolite levels. However, additional studies examining the effects of UGT genotype on overall patient response to TAM are needed to further examine the role of UGT polymorphisms in the therapeutic efficacy of TAM.

Association between UDP‐glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females

“…For example, the UGT2B7 rs7668258 C>T polymorphism has been associated with the metabolism, efficacy and toxicity of epirubicin chemotherapy in breast cancer patients . Moreover, UGT2B7 802Tyr has been suggested as a candidate biomarker for a good response to tamoxifen therapy in patients with breast cancer …”

“…The UGT2B7 gene is located on chromosome 4 and has 6 exons, with an overall length of approximately 16 kb . Polymorphisms in the UGT2B7 gene have been reported to affect the pharmacokinetics and pharmacodynamics of drugs …”

“…UGT2B7 glucuronidates a variety of endogenous compounds, including steroid hormones, bile acids and retinoids, as well as widely used drugs, such as zidovudine (AZT), morphine, mycophenolic acid, tamoxifen and oxcarbazepine. 5,[8][9][10][11][12] The UGT2B7 gene is located on chromosome 4 and has 6 exons, with an overall length of approximately 16 kb. 13 Polymorphisms in the UGT2B7 gene have been reported to affect the pharmacokinetics and pharmacodynamics of drugs.…”

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

“…This indicated that alkyl acids can competitively inhibit specific UGT isoforms, which could be used to safely reverse this drug resistance mechanism. In addition, there is a correlation between the concentrations of glucuronide metabolites of TAM in tumor tissues and UGT1A4 expression in patients with estrogen receptorpositive breast cancer (Romero-Lorca et al, 2015), in which UGT1A4 increases the glucuronidation levels of active hydroxylated TAM metabolites (4-OH-TAM-O-glucuronidation and endoxifen-glucuronidation). This modified glucuronidation shortens half-life period of circulating TAM metabolites and thus reduces their effectiveness for cancer.…”

Racial disparity in metabolic regulation of cancer

“…The genetic polymorphism of the hENT1 gene 706G→C has been associated with reduced response to gemcitabine chemotherapy and with the prognosis of NSCLC (178). Remarkably, metabolomic studies in breast cancer have revealed that patients with allelic variations in CYP2D6, SULT1A2 , UGT1A4 48Val and UGT2B7 268Tyr as best candidates for the optimal therapeutic response to tamoxifen, a chemotherapeutic prodrug, the hydroxylated and non-glucuronidatedform of which exerts anti-estrogen effects during the treatment of estrogen-dependent breast cancer (179). These examples distinctly indicate a link between inherited genetic differences to therapy responses by specific drugs.…”