Human UDP-glucuronosyltransferase, UGT1A8, glucuronidates dihydrotestosterone to a monoglucuronide and further to a structurally novel diglucuronide
Abstract
We identified human UDP-glucuronosyltransferase (UGT) isoforms responsible for producing dihydrotestosterone (DHT) diglucuronide, a novel glucuronide in which the second glucuronosyl moiety is attached at the C2' position of the first glucuronosyl moiety, leading to diglucuronosyl conjugation of a single hydroxyl group of DHT at the C17 position. Incubation of the DHT monoglucuronide with 12 cDNA-expressed recombinant human UGT isoforms and uridine 5'-diphosphoglucuronic acid resulted in a low but measurable DHT diglucuronidation activity primarily with UGT1A8, a gastrointestinal UGT, and to a lesser extent with UGT1A1 and UGT1A9. In contrast, the activity of DHT monoglucuronidation was high and was found in UGT2B17, UGT2B15, UGT1A8, and UGT1A4 in descending order. Among the 12 UGT isoforms tested, only UGT1A8 was capable of producing DHT diglucuronide from DHT. The kinetics of DHT diglucuronidation by microsomes from human liver and intestine fitted the Michaelis-Menten model, and the V(max)/K(m) value for the intestinal microsomes was approximately 4 times greater than that for the liver microsomes.
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The formation of androgen-linked di-glucuronides, in which a second glucuronidation occurs on the first glucuronosyl moiety, is possible.
“The formation of androgen linked di-glucuronides (second glucuronidation occurs on the first glucuronosyl moiety) is also possible (Murai et al., 2005, Murai et al., 2006).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Murai et al., 2006
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- Authors
- Murai, T., Samata, N., Iwabuchi, H., & Ikeda, T.
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 34
- Issue
- 7
- Pages
- 1102-1108
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2066866681
- Cited by
- 30
- References
- 29
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2019: 1 · 2018: 3 · 2017: 2 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 4
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- UGT1A8, dihydrotestosterone, glucuronidation, UGT isoforms, UGT2B17, UGT2B15, UGT1A4, UGT1A1, UGT1A9, intestinal microsomes, liver microsomes, Michaelis-Menten kinetics, drug metabolism
- MeSH terms
- UDP-Glucuronosyltransferase 1A9, UGT1A1 Enzyme, Animals, Dogs, Humans, Intestines, Isoenzymes, Kinetics, Microsomes, Liver, Recombinant Proteins, Dihydrotestosterone, Glucuronosyltransferase, Molecular Structure, Rats, In Vitro Techniques
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