Repeated glucuronidation at one hydroxyl group leads to structurally novel diglucuronides of steroid sex hormones
Abstract
Androgens (androsterone, dihydrotestosterone and testosterone) and estrogens (estradiol, estriol and estrone) were incubated with liver microsomes from rats, dogs, monkeys and humans in the presence of uridine diphosphoglucuronic acid (UDPGA), and the glucuronides produced were structurally characterized by liquid chromatography-tandem mass spectrometry. After 2-h incubation with dog liver microsomes, all substrates tested were converted (approximately 2-10%) to structurally novel diglucuronides, where two glucuronosyl groups are bound to a single hydroxyl group in tandem. Two-dimensional nuclear magnetic resonance spectroscopy unambiguously elucidated the chemical structures of the 3-O-diglucuronide of estrone and the 17-O-diglucuronide of testosterone isolated from the incubation mixture. Monkey and human liver microsomes were also found to have the activity to form this type of diglucuronide, albeit more slowly than the dog liver microsomes, but rat liver microsomes produced no detectable diglucuronides. The rate of formation of estrone 3-O-diglucuronide from the corresponding monoglucuronide in dog liver microsomes followed classical Michaelis-Menten kinetics at substrate concentrations from 50 to 1000 microM, with a K(m) value of 127.1 microM and a V(max) value of 47.0 pmol/min/mg protein.
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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., 2005
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Bichlmaier, I. (2008) · Työväentutkimus Vuosikirja
- Authors
- Murai, T., Iwabuchi, H., & Ikeda, T.
- Venue
- Drug Metabolism and Pharmacokinetics
- Published
- 2005
- Volume
- 20
- Issue
- 4
- Pages
- 282-293
- ISSN
- 1347-4367 (ISSN-L)
- OpenAlex
- W2008801566
- Cited by
- 17
- References
- 24
- Citations by year
- 2023: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2014: 2 · 2013: 1 · 2012: 3
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- glucuronidation, sex steroids, androgens, estrogen, liver microsomes, UDP-glucose, Michaelis-Menten kinetics, drug metabolism
- MeSH terms
- Animals, Haplorhini, Chromatography, Liquid, Dogs, Estrone, Humans, Kinetics, Microsomes, Liver, Magnetic Resonance Spectroscopy, Gonadal Steroid Hormones, Species Specificity, Mass Spectrometry, Testosterone, Glucuronosyltransferase, Uridine Diphosphate Glucuronic Acid, Glucuronides, Rats
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