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Cited by 131Pharmacogenetics and Drug MetabolismProstate Cancer Treatment and ResearchDrug Transport and Resistance Mechanisms

Characterization and regulation of UDP-glucuronosyltransferases in steroid target tissues

Bélanger, Alain, Hum, Dean W., Beaulieu, Martin, Lévesque, Éric, Guillemette, Chantal, Tchernof, André, Bélanger, Guy, Turgeon, David +1 more·1998·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/s0960-0760(97)00183-0
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Abstract

Conjugation of compounds by glucuronidation is a pathway found in all vertebrates studied to date. Although, it is widely recognized that the liver is a major site of glucuronidation, it is now clear that extrahepatic tissues are also involved in the conjugation of compounds to which these tissues are exposed. High levels of androsterone glucuronide and androstane-3alpha,17beta-diol glucuronide found in the human prostate, breast cyst fluid and ovary follicular fluid suggest that glucuronidation of 5alpha-reduced C19 steroids occurs in these tissues. Recently, we have reported the tissue distribution of UGT2B15, which can conjugate steroids in several human extrahepatic steroid target tissues including the skin, breast and prostate. We have also isolated a new UGT2B cDNA encoding UGT2B17, that conjugates ADT which is the major 5alpha-reduced C19 steroid glucuronide in the circulation of humans. UGT2B17 is also widely distributed in several human steroid target tissues. This gene was mapped to human chromosome 4q13 and has an exon/intron structure similar to that of rat UGT2B1 and UGT2B2. Both UGT2B15 and UGT2B17, which are able to catalyze the glucuronidation of DHT, are expressed in LNCaP cells. Interestingly, glucuronidation of steroids is markedly regulated by several factors including androgens and growth factors. Treatment of LNCaP cells with dihydrotestosterone (DHT) and epidermal growth factor (EGF) caused a decrease of DHT glucuronidation and UGT2B mRNA levels. RNase protection assays showed a specific decrease of UGT2B17 transcript in LNCaP cells treated with DHT and EGF however, the level of UGT2B15 mRNA was not affected. As well, Western blot analysis demonstrated a diminution of UGT2B17 protein level in response to DHT and EGF. These results demonstrate a differential regulation of different isoforms of steroid conjugating UGTs present in human prostate LNCaP cells. In addition, UGT2B17 was shown to be more labile than UGT2B15 indicating that regulation of UGT2B17 expression would lead to a more rapid change in the level of glucuronidated steroids. Expression of exogenous UGT2B17 in LNCaP cells by gene transfer led to a significant decrease in the androgen response. This result indicates the ability of UGT enzymes to regulate the androgen response by conjugating androgens which abolishes their interaction with their receptor and facilitates their clearance from the cell. The glucuronidation of steroids by UGT enzymes is an important mechanism by which the levels of steroids is regulated in steroid target tissues.

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Crossref · 10.1016/s0960-0760(97)00183-0

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  • The UGT2B enzymes UGTB7, UGTB15, and UGTB17, responsible for glucuronidation of DHT and its metabolites androsterone and 3α-diol, are expressed in skin.

    “The three UGT2B enzymes, UGTB7, UGTB15, UGTB17, which are responsible for the glucuronation of DHT and its metabolites, androsterone and 3α-diol are all expressed in the skin [122, 123].”

    From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [123]

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Authors
Bélanger, A., Hum, D. W., Beaulieu, M., Lévesque, É., Guillemette, C., Tchernof, A., Bélanger, G., Turgeon, D., & Dubois, S.
Affiliations
Centre hospitalier de l'Université Laval (CA)
Corresponding author
Bélanger, Alain
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
1998-04
Volume
65
Issue
1-6
Pages
301-310
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/s0960-0760(97)00183-0
OpenAlex
W2047463986
Cited by
131
References
19
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 2 · 2013: 8 · 2012: 3
FWCI
8.91
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
UDP-glucuronosyltransferase, UGT2B15, UGT2B17, androsterone glucuronide, prostate, LNCaP cells, androgen regulation, epidermal growth factor, gene expression regulation
MeSH terms
Amino Acid Sequence, Androgens, Chromosomes, Human, Pair 4, Female, Humans, Isoenzymes, Male, Molecular Sequence Data, Prostatic Neoplasms, Glucuronosyltransferase, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic

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