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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 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.
Highlights
Tamoxifen (TAM) is widely used to prevent recurrence in patients with estrogen or progesterone receptor-positive breast cancer (BC) due to its estrogen receptor blocking effect [1]
Besides our findings related to the CYP2D6 genotype, this paper presents the first data on the effects of SULT1A2 genotypes on TAM metabolite levels
Prevalences of the commonly observed CYP2D6 genotypes and alleles observed in our study are in good agreement with those reported for other European populations [29, for instance] with CYP2D6*4 being the most frequently detected null allele (12%, Table 4)
Summary
Tamoxifen (TAM) is widely used to prevent recurrence in patients with estrogen or progesterone receptor-positive breast cancer (BC) due to its estrogen receptor blocking effect [1]. N-desmethyltamoxifen (NDM-TAM), produced by CYP3A4/5-mediated metabolism, is the major primary metabolite, accounting for 90% of primary TAM oxidation, whereas 4OH-TAM, mediated by CYP2D6 activity, is a minor metabolite. Both NDM-TAM (produced via CYP2D6) and 4OH-TAM (produced via CYP3A4/5) are secondarily metabolized to endoxifen [4]. It has been established that tamoxifen and its metabolites undergo phase II conjugation reactions including glucuronidation and sulfation, few studies have examined the role of phase II sulfotransferase enzymes (SULTs) in TAM metabolism. Given that 4-OH-TAM and endoxifen are known substrates of SULT1A1 [5 and 6, respectively], different SULT enzyme activity levels could markedly influence the efficacy of TAM [5]
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