Abstract
The metabolism in primary human hepatocyte cultures often deviates from that in clinical studies, which in turn are hampered by ethical constraints. Here the use of urokinase-type plasminogen activator-severe combined immunodeficiency [uPA(+/+)-SCID] mice transplanted with human hepatocytes was investigated as a model for in vivo metabolic studies. The urinary excretion profile after oral administration of 4-androstene-3,17-dione (AD) in chimeric mice was investigated by using gas chromatography-mass spectrometry detection and was compared with previously reported metabolites of AD in humans and cell cultures. Chimeric mice exhibited an AD metabolic profile similar to that of humans, showing androsterone and etiocholanolone as major metabolites. Several hydroxylated steroids were detected as minor metabolites in the chimeric mice compared with hepatocyte cultures. A significant correlation between the extent of liver replacement and the relative abundances of human-type metabolites was established. The results for AD showed that humanized liver uPA-SCID mice can serve as an alternative model for in vivo metabolism studies in humans. In the future, this model could possibly be used for other steroids or pharmaceutical compounds.
Footnotes
This work was supported by the World Anti-Doping Agency; the Belgian Government via the Interuniversity Attraction Poles Program [P6/36–HEPRO]; the Special Research Fund of the Ghent University [Grant BOF 011D3099] (to L.L.); and a Concerted Action [Grant 01G00507]. P.M. is a postdoctoral fellow of the Research Foundation-Flanders. (Fonds Wetenschappelijk Onderzoek-Vlaanderen).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028183
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- uPA-SCID
- urokinase plasminogen activator-severe combined immunodeficiency
- hAlb
- human albumin
- AD
- 4-androstene-3,17-dione
- GC-MS
- gas chromatography-mass spectrometry
- DHT
- dihydrotestosterone
- PBS
- phosphate-buffered saline
- RSD
- relative standard deviation
- DHEA
- dehydroepiandrosterone.
- Received April 23, 2009.
- Accepted September 2, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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