Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients

• Published in: PloS one Vol. 8; no. 7; p. e70183
• Main Authors: Fernández-Santander, Ana, Gaibar, María, Novillo, Apolonia, Romero-Lorca, Alicia, Rubio, Margarita, Chicharro, Luis Miguel, Tejerina, Armando, Bandrés, Fernando
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.07.2013; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents, Hormonal - blood; Antineoplastic Agents, Hormonal - metabolism; Arylsulfotransferase - genetics; Arylsulfotransferase - metabolism; Biology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer therapies; Chromatography; Correlation analysis; CYP2D6 protein; Cytochrome; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P450; Enzymes; Estrogen; Estrogens; Estrone sulfotransferase; Female; Gene Frequency; Genotype; Genotype & phenotype; Genotypes; High-performance liquid chromatography; Humans; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medicine; Metabolism; Metabolites; Middle Aged; Neoplasm Staging; Patients; Pharmacogenetics; Plasma; Plasma levels; Polymerase chain reaction; Restriction fragment length polymorphism; Studies; Substrates; Sulfotransferase; Tamoxifen; Tamoxifen - blood; Tamoxifen - metabolism; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070183

Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.