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Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate

https://doi.org/10.1016/j.beem.2008.01.001Get rights and content

In the human prostate, dihydrotestosterone (DHT) – the natural androgen having the highest affinity for the androgen receptor – is not released directly into the systemic circulation from peripheral target tissues but it is rather converted in situ into two metabolites which have a low affinity for the androgen receptor: androsterone (ADT) and androstane-3α,17β-diol (3α-DIOL). Several clinical observations indicate that these two androgen metabolites are further inactivated in the prostate by glucuronidation. In the human, the family of UDP-glucuronosyltransferase (UGT) enzymes comprises 18 members in three subfamilies: UGT1A, UGT2A and UGT2B. Identification of the substrates for each member has revealed that three UGT2B enzymes are mainly responsible for DHT, ADT and 3α-DIOL glucuronidation: UGT2B7, UGT2B15 and UGT2B17. Tissue distribution and cellular localization of UGT2B transcripts and proteins clearly indicate that only UGT2B15 and UGT2B17 are expressed in the prostate. Using the human prostate carcinoma LNCaP cell line, it was shown that UGT2B expression and activity are negatively regulated by several factors, including androgens. On the other hand, inhibition of UGT2B115/17 expression by small interfering RNA (siRNA) resulted in an induced response to DHT of androgen-receptor target genes such as PSA, KLK4, NKX3.1, TMPRSS2, SLC16A6 and VEGF. It is suggested that the conjugating activity of UGT enzymes in androgen target tissues is a mechanism for modulating the action of steroids and/or protecting the tissues from deleterious high concentrations of androgens.

Section snippets

Phase-1 androgen metabolism: 3α-steroid dehydrogenase and 17β-steroid dehydrogenase, first step in the conversion of active to inactive androgens

The phase-1 inactivation of DHT (Figure 2) involves several possible pathways with the contribution of a 17β-HSD oxidative reaction (17β-HSD type 2) forming the 17-ketosteroid androstanedione and then the 3α-HSD type 3 reductive reaction forming androsterone (ADT), or the direct conversion of DHT via the same 3α-HSD to androstane-3α,17β-diol (3α-DIOL).8 The expression of 17β-HSD type 2 and 3α-HSD type 3 transcripts has been detected in all androgen target tissues studied so far. Using

Phase-2 enzymes: glucuronosyltransferase enzymes and complete inactivation of androgens

The glucuronidation reaction catalyzed by enzymes of the UGT superfamily corresponds to the transfer of the glucuronosyl group from UDP-glucuronic acid to small hydrophobic molecules.9 The resulting glucuronide products are more polar, generally water-soluble, less toxic, and more easily excreted from the body than is the parent compound. Based upon homology of primary structures, the UGT proteins have been categorized into two families, namely UGT1 and UGT2 (Figure 3).10

In humans, the UGT1A

Androgen glucuronides in the circulation

In humans, blood levels of non-conjugated 3α-DIOL and ADT, the two major metabolites of DHT, are below 1 ng/mL.17 Several observations published over the last 25 years clearly establish that a large portion of the androgen metabolites found in blood and urine are under the form of glucuronide derivatives.18, 19, 20, 21, *22 A liquid chromatographic/mass spectroscopic (LC-MS/MS) method for the determination in serum of 3α-diol-glucuronides and ADT-G was recently developed by our group; this

Expression of UGT2B enzymes in the prostate

The expression of UGT2B enzymes in the human prostate was studied in more detail by in situ hybridization and immunohistochemistry (Figure 4).16, *25 In the human prostate, the alveoli are composed of two epithelial cell types. The basal layer is composed of small cells located at the periphery of the alveoli, while the luminal cells are large columnar cells in contact with the alveolar lumen and lined above the continuous basal layer. The two cell types play distinct but complementary roles in

Modulation of UGT2B15/B17 gene expression and its impact on androgen concentrations and activity

Several studies using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry have demonstrated a large inter-individual variability in UGT expression in tissues including the breast, liver and gastrointestinal tract, thus suggesting that these enzymes are modulated by several factors. The presence of high glucuronidation activity in LNCaP cells, a human prostate cancer cell line, has led to the characterization of the UGT2B enzymes expressed in this cell

Polymorphism in the UGT2B15 gene and deletion of the UGT2B17 gene

In addition to the first UGT2B15(D85) isolated by Chen et al30, Levesque et al31 discovered a second form of UGT2B15, namely UGT2B15(Y85), and demonstrated that the Vmax for DHT conjugation of the Y allele is two-fold greater than the enzyme resulting from the D allele. It was then postulated that the high efficacy of the UGT2B15(Y85) enzyme in the prostate may protect the tissue from high levels of DHT and decrease the risk of prostate cancer. In 2000, MacLeod et al32 were the first to

Conclusion

In this review, the metabolism of androgens – particularly the conversion of androgens to androgen glucuronides – has been discussed. The fine regulation of the intracellular concentration of androgens in the prostate is ensured not only at the level of activation by steroidogenic enzymes but also at the level of degradation by steroid-inactivating enzymes. Two members of the UGT2B enzymes, UGT2B15/B17, are expressed in the prostate, and changes in their activity may influence the

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