Document Detail


Identification of novel roles of the cytochrome p450 system in early embryogenesis: effects on vasculogenesis and retinoic Acid homeostasis.
MedLine Citation:
PMID:  12917333     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytochrome P450-dependent monooxygenase system catalyzes the metabolism of xenobiotics and endogenous compounds, including hormones and retinoic acid. In order to establish the role of these enzymes in embryogenesis, we have inactivated the system through the deletion of the gene for the electron donor to all microsomal P450 proteins, cytochrome P450 reductase (Cpr). Mouse embryos homozygous for this deletion died in early to middle gestation (approximately 9.5 days postcoitum [dpc]) and exhibited a number of novel phenotypes, including the severe inhibition of vasculogenesis and hematopoiesis. In addition, defects in the brain, limbs, and cell types where CPR was shown to be expressed were observed. Some of the observed abnormalities have been associated with perturbations in retinoic acid homeostasis in later embryogenesis. Consistent with this possibility, embryos at 9.5 dpc had significantly elevated levels of retinoic acid and reduced levels of retinol. Further, some of the observed phenotypes could be either reversed or exacerbated by decreasing or increasing maternal retinoic acid exposure, respectively. Detailed analysis demonstrated a close relationship between the observed phenotype and the expression of genes controlling vasculogenesis. These data demonstrate that the cytochrome P450 system plays a key role in early embryonic development; this process appears to be, at least in part, controlled by regional concentrations of retinoic acid and has profound effects on blood vessel formation.
Authors:
Diana M E Otto; Colin J Henderson; Dianne Carrie; Megan Davey; Thomas E Gundersen; Rune Blomhoff; Ralf H Adams; Cheryll Tickle; C Roland Wolf
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  23     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-08-14     Completed Date:  2003-09-24     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6103-16     Citation Subset:  IM    
Affiliation:
Cancer Research UK, Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Vessels / abnormalities,  embryology*
Cytochrome P-450 Enzyme System / physiology*
Embryo, Mammalian / blood supply,  enzymology*
Fetal Death / genetics
Fibroblast Growth Factor 8
Fibroblast Growth Factors / genetics
Gene Expression Regulation, Developmental
Homeostasis / genetics
Mice
Mice, Mutant Strains
Microsomes / physiology
NADPH-Ferrihemoprotein Reductase / genetics*,  metabolism
Phenotype
Receptors, Retinoic Acid / genetics
Tretinoin / metabolism*,  pharmacology
Vitamin A / metabolism
Chemical
Reg. No./Substance:
0/Fgf8 protein, mouse; 0/Receptors, Retinoic Acid; 0/retinoic acid binding protein I, cellular; 0/retinoic acid binding protein II, cellular; 11103-57-4/Vitamin A; 148997-75-5/Fibroblast Growth Factor 8; 302-79-4/Tretinoin; 62031-54-3/Fibroblast Growth Factors; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase
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