Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans

Bélanger, Alain; Pelletier, Georges; Labrie, Fernand; Barbier, Olivier; Chouinard, Sarah

doi:10.1016/j.tem.2003.10.005

Cited by 208 publications

(192 citation statements)

References 60 publications

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“…Thus, circulating testosterone taken up from the circulation is converted by 5␣-reductase to dihydrotestosterone (DHT), 4 the natural androgen receptor agonist (1). There is clear evidence now that adrenal steroid precursors, namely dehydroepiandrosterone and its sulfate, are converted to testosterone in several tissues (2,3). The observation that the DHT concentration in prostate is only decreased by 50% in castrated patients treated for prostate cancer further support the role of adrenal steroid precursors as a source of androgens (4 -6).…”

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“…The observation that the DHT concentration in prostate is only decreased by 50% in castrated patients treated for prostate cancer further support the role of adrenal steroid precursors as a source of androgens (4 -6). These findings of local transformation of circulating steroids into bioactive testosterone and DHT have been integrated in the process called "intracrinology," where several steroidogenic enzymes, including 3␣-hydroxysteroid dehydrogenase-⌬4 -5 isomerase (3␣-HSD type 1), 17␤-HSDs, and 5␣-reductase, contribute to the formation of DHT (2,7). Growing evidence indicates that tissue DHT concentrations are also modulated by 3␣-hydroxysteroid dehydrogenase (3␣-HSD) type 3 and 17␤-HSD type 7, which form inactive androstane-3␣,17␤-diol (3␣-DIOL) and androsterone (ADT) (8,9).…”

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confidence: 99%

“…UGT2B7 and -B17 conjugate ADT at the position 3-hydroxyl, whereas only UGT2B7 forms 3␣-DIOL-3-glucuronide. UGT2B15 and -B17 specifically conjugate DHT and 3␣-DIOL at the 17-hydroxyl position (2,17). 3␣-DIOL-17G is the predominant form of circulating 3␣-DIOL-glucuronide in adult men and has been identified as a strong predicator of prostate volume (18).…”

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“…In androgen-dependent prostate cancer cells, LNCaP, UGT2B15 and -B17 are highly expressed (17) and the conjugation of androgen metabolites such as DHT, 3␣-DIOL, and ADT have been demonstrated (2,25). The presence of UGT2B15/ B17 in LNCaP cells was particularly useful to investigate the regulation of their expression by several factors, including androgen, growth factors, and cytokines (17, 26 -28).…”

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UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Chouinard

Barbier

Bélanger

2007

Journal of Biological Chemistry

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Uridine diphosphate-glucuronosyltransferase 2 (UGT2)B15 and B17 enzymes conjugate dihydrotestosterone (DHT) and its metabolites androstane-3␣,17␤-diol (3␣-DIOL) and androsterone (ADT). The presence of UGT2B15/B17 in the epithelial cells of the human prostate has been clearly demonstrated, and significant 3␣-DIOL glucuronide and ADT-glucuronide concentrations have been detected in this tissue. The human androgen-dependent cancer cell line, LNCaP, expresses UGT2B15 and -B17 and is also capable of conjugating androgens. To assess the impact of these two genes in the inactivation of androgens in LNCaP cells, their expression was inhibited using RNA interference. The efficient inhibitory effects of a UGT2B15/B17 small interfering RNA (siRNA) probe was established by the 70% reduction of these UGT mRNA levels, which was further confirmed at the protein levels. The glucuronidation of dihydrotestosterone (DHT), 3␣-DIOL, and ADT by LNCaP cell homogenates was reduced by more than 75% in UGT2B15/B17 siRNA-transfected LNCaP cells when compared with cells transfected with a nontarget probe. In UGT2B15/B17-deficient LNCaP cells, we observe a stronger response to DHT than in control cells, as determined by cell proliferation and expression of eight known androgen-sensitive genes. As expected, the amounts of DHT in cell culture media from control cells were significantly lower than that from UGT2B15/B17 siRNA-treated cells, which was caused by a higher conversion to its corresponding glucuronide derivative. Taken together these data support the idea that UGT2B15 and -B17 are critical enzymes for the local inactivation of androgens and that glucuronidation is a major determinant of androgen action in prostate cells.Production and secretion of testosterone by the testis has long been considered one of the major factors influencing androgen function in androgen target tissues, namely, the prostate. Thus, circulating testosterone taken up from the circulation is converted by 5␣-reductase to dihydrotestosterone (DHT), 4 the natural androgen receptor agonist (1). There is clear evidence now that adrenal steroid precursors, namely dehydroepiandrosterone and its sulfate, are converted to testosterone in several tissues (2, 3). The observation that the DHT concentration in prostate is only decreased by 50% in castrated patients treated for prostate cancer further support the role of adrenal steroid precursors as a source of androgens (4 -6). These findings of local transformation of circulating steroids into bioactive testosterone and DHT have been integrated in the process called "intracrinology," where several steroidogenic enzymes, including 3␣-hydroxysteroid dehydrogenase-⌬4 -5 isomerase (3␣-HSD type 1), 17␤-HSDs, and 5␣-reductase, contribute to the formation of DHT (2, 7). Growing evidence indicates that tissue DHT concentrations are also modulated by 3␣-hydroxysteroid dehydrogenase (3␣-HSD) type 3 and 17␤-HSD type 7, which form inactive androstane-3␣,17␤-diol (3␣-DIOL) and androsterone (ADT) (8, 9). Although extremely important in...

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UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Chouinard

Barbier

Bélanger

2007

Journal of Biological Chemistry

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“…ADS is clinically recognized as one of the major androgen metabolites found in urine. AD sulfation, enabling ADS formation, has been considered as one of the major catabolic processes of androgens in human liver before urinary excretion [5,6]. Elimination of steroids from the body via urine is achieved by the transformation of the steroid structure and/or by the formation of glucuronide or sulfate conjugates.…”

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Unique potentiometric detection systems for HPLC determination of some steroids in human urine

Vissers¹,

Everaert²,

Sekuła³

et al. 2009

J of Separation Science

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Unique potentiometric detection systems for HPLC determination of some steroids in human urineIsocratic HPLC with potentiometric detection is used for the determination of some 17-ketosteroids (17-KS), e.g., androsterone, dehydroepiandrosterone and estrone, and their respective sulfated conjugates (17-KSS). Glassy carbon or composite electrodes containing a mixture of graphite and poly(vinyl chloride), PVC, were used as substrate electrodes. These substrates were covered either by montmorillonite or potassium tetrakis(p-chlorophenyl) borate containing PVC-based rubber phase membranes. The neutral 17-KS compounds were derivatized with Girard's reagent P (GP) to obtain cationic pyridinium acetohydrazones prior to the HPLC/potentiometric detection assay. No side reactions were observed, and the GP itself was not interfering. The method yielded accurate and reproducible results and was applicable to samples containing down to micromolar concentrations. Next, the 17-KSS compounds, acting as anionic charged molecules, were determined directly in human urine samples with the HPLC/potentiometry combination without preliminary derivatization. For this purpose, a new anion-sensitive potentiometric electrode was developed using a macrocyclic polyamine containing, PVC-based, rubber phase membrane. The three 17-KSS compounds were also determined accurately down to micromolar concentrations. Especially, the main androgen metabolites as dehydroepiandrosterone sulfate and androsterone sulfate could be selectively determined with a developed potentiometric sensor in human urine samples without time-consuming cleanup and preconcentration step. IntroductionThe 17-ketosteroids (17-KS) are steroids with a ketone functional group at position 17 in their polycyclic carbon skeleton. Typical examples are dehydroepiandrosterone (DHEA), estrone (E 1 ), and androsterone (AD), see Scheme (1) for their structures. DHEA, a representative 17-KS, is synthesized by the adrenal gland and then converted into active hormones, estrogens, and androgens, in the peripheral tissues. Most of the DHEA (over 99%) is present in the blood as the sulfated conjugate (dehydroepiandrosterone sulfate (DHEAS)), which is second to cholesterol in abundance for circulating steroids in humans. In both sexes, serum DHEA levels vary profoundly throughout life. Levels start to increase in children, peakCorrespondence: Professor Grzegorz Bazylak, Department of Pharmaco-Bromatology & Molecular Nutrition, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jagiellonska 13, PL-85-067 Bydgoszcz, Poland E-mail: gbazylak@cm.umk.pl Fax: +4852-585-3817Abbreviations: AD, androsterone; AD-GP, androsterone derivatized with Girard's reagent P; ADS, androsterone sulfate; BOR_-Comp, TCPB containing graphite/PVC composite electrode used in repeated over several days measurements of sequence of different injected concentration of the analyte; BOR_Comp_1-day, TCPB containing graphite/PVC composite electrode used in consequtive measurements of the same injected concent...

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Nuclear Receptor‐Mediated Regulation of Phase II Conjugating Enzymes

Barbier

2008

Nuclear Receptors in Drug Metabolism

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Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans

Cited by 208 publications

References 60 publications

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Unique potentiometric detection systems for HPLC determination of some steroids in human urine

Nuclear Receptor‐Mediated Regulation of Phase II Conjugating Enzymes

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