RGD Reference Report - Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors. - Rat Genome Database

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Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors.

Authors: Nguyen, X  Wang, MH  Reddy, KM  Falck, JR  Schwartzman, ML 
Citation: Nguyen X, etal., Am J Physiol. 1999 Jun;276(6 Pt 2):R1691-700.
RGD ID: 2303410
Pubmed: PMID:10362749   (View Abstract at PubMed)

20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A omega-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and -4A8 cDNAs, using baculovirus and Sf 9 insect cells. Arachidonic acid omega- and omega-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM-1. min-1 for CYP4A1 was followed by 72 and 22 nM-1. min-1 for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an omega-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid omega-hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform-specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20-HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11, 12-epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.



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Biological Process

  

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp4a1Ratlinoleic acid metabolic pathway  IDA  RGD 
Cyp4a2Ratlinoleic acid metabolic pathway  IDA  RGD 
Cyp4a3Ratlinoleic acid metabolic pathway  IDA  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cyp4a1  (cytochrome P450, family 4, subfamily a, polypeptide 1)
Cyp4a2  (cytochrome P450, family 4, subfamily a, polypeptide 2)
Cyp4a3  (cytochrome P450, family 4, subfamily a, polypeptide 3)
Cyp4a8  (cytochrome P450, family 4, subfamily a, polypeptide 8)


Additional Information