752: Tissue Expression and Breed-Related Pharmocogenetics of Cytochrome P450 3A12

Grant Status: Closed

Grant Amount: $88,269.38
Dr. Joshua M. Akey,, University of Washington
September 1, 2007 - August 31, 2009
Breed(s): -All Dogs
Research Program Area: Treatment

Project Summary

Although many factors influence a patient�s response to drug therapy, including the patient�s age, disease status, concurrent medications, and others, these are insufficient to explain the wide variation in drug response observed between patients. In humans, genetics has been shown to be an extremely important factor in determining whether or not a patient will experience an adverse drug reaction (ADR). In dogs, many ADRs are known to be breedrelated. That is, drugs that are tolerated by most dogs may cause ADRs in certain breeds. Our research focuses on two important drug metabolizing enzymes in dogs. We have shown that these enzymes are expressed not only in the liver but also in the small intestine. Our CHF supported research project has completed all of its objectives, which has provided critically needed new insights into the expression patterns and genetic variation of CYP3A12 within and among dog breeds. These data have provided the necessary framework for correlating patterns of DNA sequence and structural variation of CYP3A12 with drug metabolizing phenotypes and breed-specific ADRs.

Publication(s)

Mealey KL, Jabbes M, Spencer E, Akey JM. (2008) Differential expression of CYP3A12 and CYP3A26 in canine liver and intestine. Xenobiotica. Xenobiotica. 38:1305-1312. Nicholas TJ, Cheng Z, Ventura M, Mealey K, Eichler EE, and Akey JM. (2009) The genomic architecture of segmental duplications and copy number variants in dogs. Genome Research. 19:491-499. Akey, J.M., Ruhe, A.L., Akey, D.T., Wong, A.K., Connelly, C.F., Madeoy, J., Nicholas, T.J., Neff, M.W., 2010, Tracking footprints of artificial selection in the dog genome. Proceedings of the National Academy of Sciences 107, 1160-1165. Nicholas, T.J., Cheng, Z., Ventura, M., Mealey, K., Eichler, E.E., Akey, J.M., 2009, The genomic architecture of segmental duplications and associated copy number variants in dogs. Genome Research 19, 491-499.

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