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ToxSci Advance Access published online on May 4, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl009
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 8, 2006
Accepted May 2, 2006

Biotransformation and Toxicokinetics

Cloning, Tissue Expression and Regulation of Beagle Dog CYP4A Genes

Richard A. Graham 1 *, Bryan Goodwin 2, Raymond V. Merrihew 2, Wojciech L. Krol 3, and Edward L. LeCluyse 4

1 Division of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; MV CEDD DMPK, GlaxoSmithKline, RTP, NC 27709
2 Discovery Research GlaxoSmithKline, RTP, NC 27709
3 MV CEDD DMPK, GlaxoSmithKline, RTP, NC 27709
4 CellzDirect, Inc., 480 Hillsboro Street, Suite 130, Pittsboro, NC 27312

* To whom correspondence should be addressed.
Richard A. Graham, E-mail: richard.a.graham{at}gsk.com


  Abstract

In addition to its function as a fatty acid hydroxylase the peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) target gene, CYP4A, has been shown to be important in conversion of arachidonic acid to the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), 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 liver was determined. Open reading frame analysis predicted that CYP4A37, CYP4A38 and CYP4A39 are each comprised of 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{alpha} agonists GW7647X and clofibric acid resulted in an increase in CYP4A37, CYP4A38 and CYP4A39 mRNA expression (up to 4-fold), 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{alpha} agonists, similar to the human CYP4A11 gene.

Keywords: CYP4A; beagle dog; induction; PPAR{alpha}; GW7647X; clofibric acid.
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