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The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione

Leen Lootens UGent, Peter Van Eenoo UGent, Philip Meuleman UGent, Geert Leroux-Roels UGent and Frans Delbeke UGent (2009) DRUG METABOLISM AND DISPOSITION. 37(12). p.2367-2374
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
CHIMERIC MICE, UPA-SCID MOUSE, MEN, ANDROSTENEDIONE, ENZYMES, STEROIDS, INDUCTION, EXPRESSION, CYTOCHROME-P450, EPITESTOSTERONE
journal title
DRUG METABOLISM AND DISPOSITION
Drug Metab. Dispos.
volume
37
issue
12
pages
2367 - 2374
Web of Science type
Article
Web of Science id
000271935200013
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.743 (2009)
JCR rank
45/236 (2009)
JCR quartile
1 (2009)
ISSN
0090-9556
DOI
10.1124/dmd.109.028183
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
843293
handle
http://hdl.handle.net/1854/LU-843293
date created
2010-01-27 15:48:34
date last changed
2011-04-13 16:07:28
@article{843293,
  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.},
  author       = {Lootens, Leen and Van Eenoo, Peter and Meuleman, Philip and Leroux-Roels, Geert and Delbeke, Frans},
  issn         = {0090-9556},
  journal      = {DRUG METABOLISM AND DISPOSITION},
  keyword      = {CHIMERIC MICE,UPA-SCID MOUSE,MEN,ANDROSTENEDIONE,ENZYMES,STEROIDS,INDUCTION,EXPRESSION,CYTOCHROME-P450,EPITESTOSTERONE},
  language     = {eng},
  number       = {12},
  pages        = {2367--2374},
  title        = {The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione},
  url          = {http://dx.doi.org/10.1124/dmd.109.028183},
  volume       = {37},
  year         = {2009},
}

Chicago
Lootens, Leen, Peter Van Eenoo, Philip Meuleman, Geert Leroux-Roels, and Frans Delbeke. 2009. “The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-androstene-3,17-dione.” Drug Metabolism and Disposition 37 (12): 2367–2374.
APA
Lootens, L., Van Eenoo, P., Meuleman, P., Leroux-Roels, G., & Delbeke, F. (2009). The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione. DRUG METABOLISM AND DISPOSITION, 37(12), 2367–2374.
Vancouver
1.
Lootens L, Van Eenoo P, Meuleman P, Leroux-Roels G, Delbeke F. The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione. DRUG METABOLISM AND DISPOSITION. 2009;37(12):2367–74.
MLA
Lootens, Leen, Peter Van Eenoo, Philip Meuleman, et al. “The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-androstene-3,17-dione.” DRUG METABOLISM AND DISPOSITION 37.12 (2009): 2367–2374. Print.