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

Abstract

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 <I>CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2</I> and <I>SULT1E1</I> 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 <I>CYP2D6</I> compared to the v/v <I>CYP2D6</I> genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among <I>CYP2D6</I> genotypes. Patients featuring the <I>SULT1A2*2</I> and <I>SULT1A2*3</I> 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 <I>CYP2D6</I> genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, <I>SULT1A2</I> also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.