Document Detail


Hypoxia-induced production of 12-hydroxyeicosanoids in the corneal epithelium: involvement of a cytochrome P-4504B1 isoform.
MedLine Citation:
PMID:  10336559     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The corneal epithelium metabolizes arachidonic acid by a cytochrome P-450 (CYP)-mediated activity to 12-hydroxy-5,8,11, 14-eicosatetraenoic acid (12(R)-HETE) and 12-hydroxy-5,8, 14-eicosatrienoic acid (12(R)-HETrE ). Both metabolites possess potent inflammatory properties, with 12(R)-HETrE being a powerful angiogenic factor, and they assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea in vivo and in vitro. We used a model of corneal organ culture that exhibits hypoxia-induced epithelial CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis for isolating, identifying, and characterizing the CYP protein responsible for these eicosanoid syntheses. Northern analysis revealed the presence of a CYP4A-hybridizable mRNA, the levels of which were increased after hypoxia. Reverse transcription-polymerase chain reaction analysis with primers specific for the CYP4A family led to the isolation of a 671-base pair fragment with a 98.8% sequence homology to the rabbit lung CYP4B1 isoform, of which the levels in the corneal epithelium were greatly increased under hypoxic conditions. Moreover, phenobarbital, an inducer of hepatic CYP4B1 in the rabbit, also induced 12-HETE and 12-HETrE synthesis. Antibodies against CYP4B1, but not against CYP4A1, inhibited hypoxia-, clofibrate-, and phenobarbital-induced 12-HETE and 12-HETrE synthesis. These results suggest the involvement of a CYP4B1 isoform in the corneal epithelial synthesis of these eicosanoids in response to hypoxia.
Authors:
V Mastyugin; E Aversa; A Bonazzi; C Vafaes; P Mieyal; M L Schwartzman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  289     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-06-15     Completed Date:  1999-06-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1611-9     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AF176914
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MeSH Terms
Descriptor/Qualifier:
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / biosynthesis,  metabolism*
Alkane 1-Monooxygenase
Animals
Arachidonic Acid / metabolism
Aryl Hydrocarbon Hydroxylases*
Base Sequence
Cell Hypoxia / physiology*
Clofibrate / pharmacology
Cloning, Molecular
Cytochrome P-450 Enzyme System / genetics*,  metabolism*
DNA, Complementary
Epithelium, Corneal / drug effects,  metabolism*
Female
Isoenzymes / genetics,  metabolism
Lung / enzymology
Male
Mixed Function Oxygenases / genetics,  metabolism
Molecular Sequence Data
Organ Culture Techniques
Phenobarbital / pharmacology
Polymerase Chain Reaction
RNA, Messenger / metabolism
Rabbits
Sequence Alignment
Sequence Homology, Nucleic Acid
Stereoisomerism
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
EY06513/EY/NEI NIH HHS; HL34300/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Isoenzymes; 0/RNA, Messenger; 50-06-6/Phenobarbital; 506-32-1/Arachidonic Acid; 59985-28-3/12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 637-07-0/Clofibrate; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/cytochrome P-450 CYP4B1; EC 1.14.15.3/Alkane 1-Monooxygenase

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