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

Abstract

The oxidative metabolism of estrone (E 1 ) and estradiol (E 2 ) 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 (H 268 Y), 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 À79 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 C 277 Y) and UGT1A9 (*3 M 33 T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the À79A 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 E 2 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)

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

“…This finding suggests that glucuronidation is essential for controlling the levels of E 2 in the breast and for the protection against oxidation to genotoxic 4-OH-E 1 molecules. Furthermore, the interindividual differences in UGT1A10 and UGT2B7 expression and activity may be due to polymorphic regulation of these UGT genes that have been extensively researched [11,25,42,43]. As a consequence, the interindividual differences in UGT expression and activity could potentially modify the cellular defense potential of the breast against free oxygen radicals produced during redox cycling between the semiquinone and quinone intermediates of the catecholestrogens, thereby affecting breast cancer predisposition [30,44].…”

“…Of the UGTs identified, UGT1A10 has been established as the major UGT isoform that conjugates all the studied estrogens and UGT2B7 conjugated the genotoxic 4-OHE 1 with relatively high activity [20]. To date, UGT1A1, 1A3, 1A4, 1A8, 1A9, 2B4, 2B7, 2B15 and 2B28 have been characterized in breast tissues and/or breast cell lines [23][24][25][26][27][28][29]. However, to our knowledge, no studies have investigated the expression of UGT1A10 in any estrogen target tissue, including breast.…”

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

“…UGT2B7 is an enzyme responsible for detoxification of xenobiotics, including drugs such as morphine, efavirenz, zidovudine, and fenofibric acid, and is involved in the homeostasis of endogenous molecules like eicosanoids, bile acids, and sex steroids (Jin et al, 1997;Barbier et al, 2000;Stone et al, 2003;Turgeon et al, 2003;Thibaudeau et al, 2006;Mano et al, 2007;Bélanger et al, 2009;Tojcic et al, 2009;Trottier et al, 2013). Its expression is high in liver and kidney, but is also detectable in the gastrointestinal tract and peripheral tissues (Nakamura et al, 2008;Court et al, 2012).…”

Oligomerization of the UDP-glucuronosyltransferase 1A Proteins

“…The UGT2A proteins are localized to the olfactory system and are felt to be important in eliminating olfactory stimuli (6). The UGT2B proteins are involved in the metabolism of endogenous compounds such as bile acids (7), steroids (8), hormones (9), and fatty acids but are also important for the elimination of therapeutic drugs (10). In contrast, the UGT1 locus is located on chromosome 2q37 (11), and its gene products are linked to the metabolism of exogenous compounds, although UGT1A1 is the only UGT capable of conjugating the heme byproduct bilirubin (12).…”