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Oncology and Molecular Endocrinology Research Center (D.T., J.-S.C., É.L., D.W.H., A.B.) and Medical Research Council Group in Molecular Endocrinology (A.B.), CHUL Research Center, Laval University, Québec, Canada G1V 4G2.
Address all correspondence and requests for reprints to: Dr. Alain Bélanger, Oncology and Molecular Endocrinology Research Center, CHUL Research Center, 2705 boulevard Laurier, Québec, Canada G1V 4G2. E-mail: alain.belanger{at}crchul.ulaval.ca
Androgens and estrogens play major roles in cell differentiation, cell
growth, and peptide secretion in steroid target tissues. In addition to
the binding of these hormones to their receptors, formation and
metabolism are important in the action of steroids. Metabolism of the
potent steroid hormones includes glucuronidation, a major pathway of
steroid elimination in liver and several steroid target tissues.
Glucuronidation is catalyzed by UDP-glucuronosyltransferases (UGTs),
which transfer the polar moiety from UDP-glucuronic acid to a wide
variety of endogenous compounds, including steroid hormones. The UGT
superfamily of enzymes is subdivided into two families, UGT1 and UGT2,
on the basis of sequence homology. To date, six UGT2B proteins have
been isolated, namely UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, and
UGT2B17, all of which have been demonstrated to be active on steroid
molecules, except for UGT2B10 and UGT2B11, for which no substrate was
found. The relative activity of these enzymes on steroidal compounds
remains unknown due to variable levels of UGT2B expression in different
in vitro cell line models and various conditions of the
enzymatic assays. Comparison of the glucuronidation rates of these
enzymes requires a unique system for UGT2B protein expression, protein
normalization, and enzymatic assays. In this study we have stably
expressed UGT2B4, UGT2B7, UGT2B15, and UGT2B17 in the HK293 cell line,
which is devoid of steroid UGT activity; characterized their kinetic
properties relative to UGT protein expression; determined their
transcript and protein stabilities; and established extensively their
tissular distributions. UGT2B7 was demonstrated to glucuronidate
estrogens, catechol estrogens, and androstane-3
,17ß-diol more
efficiently than any other human UGTB isoform. UGT2B15 and UGT2B17
showed similar glucuronidation activity for androstane-3,17ß-diol
(30% lower than that of UGT2B7), whereas UGT2B17 demonstrated the
highest activity for androsterone, testosterone, and
dihydrotestosterone. UGT2B4 demonstrates reactivity toward 5-reduced
androgens and catechol estrogens, but at a significantly lower level
than UGT2B7, 2B15, and 2B17. Cycloheximide treatment of stably
transfected HK293 cells demonstrated that the UGT2B17 protein is more
labile than the other enzymes; the protein levels decrease after 1
h of treatment, whereas other UGT2B proteins were stable for at least
12 h. Treatment of stable cells with actinomycin D reveals that
UGT2B transcripts are stable for 12 h, except for the UGT2B4
transcript, which was decreased by 50% after the 12-h incubation
period. Tissue distribution of the UGT2B enzymes demonstrated that
UGT2B isoforms are expressed in the liver as well as in several
extrahepatic steroid target tissues, namely, kidney, breast, lung, and
prostate. This study clearly demonstrates the relative activities and
the major substrates of human steroid-metabolizing UGT2B enzymes, which
are expressed in a wide variety of steroid target tissues.
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D. Turgeon, J.-S. Carrier, S. Chouinard, and A. Belanger Glucuronidation Activity of the UGT2B17 Enzyme toward Xenobiotics Drug Metab. Dispos., May 1, 2003; 31(5): 670 - 676. [Abstract] [Full Text] [PDF]
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 F. Labrie, V. Luu-The, C. Labrie, A. Belanger, J. Simard, S.-X. Lin, and G. Pelletier Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone Endocr. Rev., April 1, 2003; 24(2): 152 - 182. [Abstract] [Full Text] [PDF]
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H. Inoue, G. Yuki, H. Yokota, and S. Kato Bisphenol A Glucuronidation and Absorption in Rat Intestine Drug Metab. Dispos., January 1, 2003; 31(1): 140 - 144. [Abstract] [Full Text] [PDF]
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M. H. Court, S. X. Duan, C. Guillemette, K. Journault, S. Krishnaswamy, L. L. von Moltke, and D. J. Greenblatt Stereoselective Conjugation of Oxazepam by Human UDP-Glucuronosyltransferases (UGTs): S-Oxazepam Is Glucuronidated by UGT2B15, While R-Oxazepam Is Glucuronidated by UGT2B7 and UGT1A9 Drug Metab. Dispos., November 1, 2002; 30(11): 1257 - 1265. [Abstract] [Full Text] [PDF]
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 J.-F. Gagne, V. Montminy, P. Belanger, K. Journault, G. Gaucher, and C. Guillemette Common Human UGT1A Polymorphisms and the Altered Metabolism of Irinotecan Active Metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38) Mol. Pharmacol., September 1, 2002; 62(3): 608 - 617. [Abstract] [Full Text] [PDF]
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P. A. Gregory and P. I. Mackenzie The Homeodomain Pbx2-Prep1 Complex Modulates Hepatocyte Nuclear Factor 1alpha -Mediated Activation of the UDP-Glucuronosyltransferase 2B17 Gene Mol. Pharmacol., July 1, 2002; 62(1): 154 - 161. [Abstract] [Full Text] [PDF]
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 S. A. Gestl, M. D. Green, D. A. Shearer, E. Frauenhoffer, T. R. Tephly, and J. Weisz Expression of UGT2B7, a UDP-Glucuronosyltransferase Implicated in the Metabolism of 4-Hydroxyestrone and All-Trans Retinoic Acid, in Normal Human Breast Parenchyma and in Invasive and in Situ Breast Cancers Am. J. Pathol., April 1, 2002; 160(4): 1467 - 1479. [Abstract] [Full Text] [PDF]
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