Human uridine diphosphate-glucuronosyltransferase UGT2B7 conjugates mineralocorticoid and glucocorticoid metabolites
Abstract
Mineralocorticoid and glucocorticoid hormones are metabolized as glucuronide conjugates. Using labeled [(14)C]uridine diphosphate glucuronic acid and microsomal preparations from human embryonic kidney 293 cells stably expressing the different human and monkey uridine diphosphate glucuronosyltransferase (UGT)2B enzymes, it is demonstrated that the two human allelic variants UGT2B7H((268)) and UGT2B7Y((268)) conjugate aldosterone, its A-ring reduced metabolites (5alpha-dihydroaldosterone and 3alpha,5beta-tetrahydroaldosterone), and both 5alpha- and 5beta-tetrahydrocortisone epimers. The two variants of UGT2B4 also glucuronidate tetrahydroaldosterone, whereas all enzymes tested were inefficient to produce cortisol glucuronide derivatives. Kinetic analyses reveal that UGT2B7 polymorphisms glucuronidate mineralocorticoids with a 5.5- to 20-fold higher affinity than glucocorticoids. For the first time, a significant difference between the two allelic variants of UGT2B7 is described, because UGT2B7H((268)) possesses an 11-fold higher aldosterone glucuronidation efficiency (ratio Vmax((app.))/Km((app.))) than UGT2B7Y((268)). RT-PCR experiments demonstrate the expression of UGT2B7 in human kidney and in renal proximal tubule epithelial cells, suggesting that mineralocorticoids and glucocorticoids are metabolized in their target tissue. Measurement of aldosterone glucuronidation and normalization with the UGT2B protein contents in monkey tissues demonstrate that liver and kidney glucuronidate this hormone with a similar velocity. Immunohistochemical studies performed in monkey kidney cortex reveal a restrictive expression of UGT2B proteins in the epithelial cells of the proximal tubules. Because expression of the mineralocorticoid receptor was detected in the distal tubule epithelial cells, the present data suggest a two-cell mechanism of aldosterone action and metabolism in the kidney.
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UGT2B7 has been shown to efficiently catalyze the conjugation of glucocorticoids.
“UGT2B7 has been shown to efficiently catalyze the conjugation of glucocorticoids [224].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [224]
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- Authors
- Girard, C., Barbier, O., Veilleux, G., El-Alfy, M., & Bélanger, A.
- Affiliations
- Centre hospitalier de l'Université Laval (CA)
- Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Québec, Canada G1V 4G2
- ORCID
- Barbier, Olivier
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2003-06-01
- Volume
- 144
- Issue
- 6
- Pages
- 2659-2668
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2101025406
- Cited by
- 45
- References
- 70
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 3 · 2022: 1 · 2020: 2 · 2019: 6 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 2
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Université Laval
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- UGT2B7, UGT2B4, glucocorticoid metabolism, enzyme kinetics, proximal tubular epithelial cells, renal cortex, mineralocorticoid receptor, glucuronide conjugates
- MeSH terms
- Aldosterone, Animals, Antibodies, Glucocorticoids, Humans, Kidney Cortex, Kidney Tubules, Liver, Macaca fascicularis, Male, Mineralocorticoids, RNA, Messenger, Glucuronosyltransferase, Gene Expression Regulation, Enzymologic, Glucuronides
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