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Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone

¹ Canada Research Chair in Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUQ Research Center, Faculty of Pharmacy, ² Oncology and Molecular Endocrinology Research Center, CHUQ Research Center, Faculty of Medicine, ³ Gynecologic Oncology Service, Hôtel-Dieu de Québec, Faculty of Medicine, ⁴ Population Health Research Unit, Hôpital Saint-Sacrement du CHA de Québec and Faculty of Medicine, ⁵ Department of Pathology, Hôtel-Dieu de Québec, Faculty of Medicine, ⁶ Anatomic-Pathological and Cytological Laboratory, Hôpital Saint-Sacrement, Faculty of Medicine and ⁷ Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec, Canada

Requests for reprints: Chantal Guillemette, Canada Research Chair in Pharmacogenomics, Pharmacogenomics Laboratory, CHUQ Research Center, T3-67, 2705 Boulevard Laurier, Quebec, Canada G1V 4G2. Phone: 418-654-2296; Fax: 418-654-2761; E-mail: chantal.guillemette{at}crchul.ulaval.ca.

The oxidative metabolism of estrone (E₁) and estradiol (E₂) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H²⁶⁸Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (V_max) and affinities (K_m). The –79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C²⁷⁷Y) and UGT1A9 (*3 M³³T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the –79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE–induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E₂ and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)

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