ToxSci Advance Access originally published online on May 4, 2006
Toxicological Sciences 2006 92(2):356-367; doi:10.1093/toxsci/kfl009
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Cloning, Tissue Expression, and Regulation of Beagle Dog CYP4A Genes
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* Division of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; MV CEDD DMPK and Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709; and CellzDirect, Inc., Pittsboro, North Carolina 27312
Received March 8, 2006; accepted May 2, 2006
In addition to its function as a fatty acid hydroxylase, the peroxisome proliferator-activated receptor 
(PPAR) target gene, CYP4A, has been shown to be important in the conversion of arachidonic acid to the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, suggesting a role for this enzyme in mediating vascular tone. In the present study, the cDNA sequence of beagle dog CYP4A37, CYP4A38, and CYP4A39 from the liver was determined. Open reading frame analysis predicted that CYP4A37, CYP4A38, and CYP4A39 each comprised 510 amino acids with 
90% sequence identity to one another, and 71 and 78% sequence identity to rat CYP4A1 and human CYP4A11, respectively. PCR analysis revealed that the three dog CYP4A isoforms are expressed in kidney > liver >> lung >> intestine > skeletal muscle > heart. Treatment of primary dog hepatocytes with the PPAR agonists GW7647X and clofibric acid resulted in an increase in CYP4A37, CYP4A38, and CYP4A39 mRNA expression (up to fourfold), whereas HMG-CoA synthase mRNA expression was increased to a greater extent (up to 10-fold). These results suggest that dog CYP4A37, CYP4A38, and CYP4A39 are expressed in a tissue-dependent manner and that beagle dog CYP4A is not highly inducible by PPAR agonists, similar to the human CYP4A11 gene.
Key Words: CYP4A; beagle dog; induction; PPAR; GW7647X; clofibric acid.
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