Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone.
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 (Vmax) and affinities (Km). 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.
Thibaudeau
Jean
J
Oncology and Molecular Endocrinology Research Center, Faculty of Pharmacy, Laval University, Quebec, Canada.
Lépine
Johanie
J
Tojcic
Jelena
J
Duguay
Yannick
Y
Pelletier
Georges
G
Plante
Marie
M
Brisson
Jacques
J
Têtu
Bernard
B
Jacob
Simon
S
Perusse
Louis
L
Bélanger
Alain
A
Guillemette
Chantal
C
D001711:Biotransformation; D001940:Breast / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D003062:Codon; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism*; D002393:Estrogens, Catechol; D004970:Estrone / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism*; D006900:Hydroxylation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D015810:Linkage Disequilibrium; D014599:Uterus / Q000201:enzymology / Q000378:metabolism
D003062:Codon; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; D007527:Isoenzymes; D004970:Estrone; C026418:4-hydroxyestrone; D004958:Estradiol; C014036:4-hydroxyestradiol; D014453:Glucuronosyltransferase