resistance to the toxic effects of these agents (Lasseur et al. 2007 ). It is thought that
warfarin resistance is multifactorial, largely due to mutations in the gene encoding
vitamin K epoxide oxidoreductase complex subunit 1 (VKORC1), which is the
principal target for inhibition by warfarin (Pelz et al. 2005 ). About 10 mutations
have been found so far inVKORC1in rats, with different mutations or mutation
combinations existing in different populations, resulting in a wide (approximately
40-fold) variability inKi(inhibitory constant) values for inhibition by warfarin (Pelz
et al. 2005 ; Lasseur et al. 2007 ). Amino acids 128 and 139 appear to be “hotspots”
for mutation, with 2 and 3 different mutations at these positions, respectively,
identified so far, with the most potent resistance resulting from the Y139F mutation
(Pelz et al. 2005 ). In addition to mutations directly affecting VKORC1 inhibition
potency, reducedVKORC1mRNA levels have been detected in some animals
(Lasseur et al. 2007 ). In human patients being treated with warfarin, warfarin
resistance, as reflected by a significantly higher dose being needed to achieve
effective anticoagulation, appears primarily to be the result of a polymorphism in
theVKORC1gene enhancer region that appears to enhance binding of a repressive
transcriptional factor and decrease gene expression (Yuan et al. 2005 ).
4 Future Directions
The main long-term goal of pharmacogenomics for all species is “personalised
medicine” – i.e. therapeutics tailored to the individual characteristics of the patient.
To this end, predictive algorithms incorporating genetic profiles, as well as other
critical patient information would be developed to predict drug responders, non-
responders and those that may be prone to adverse drug side-effects, as has recently
been developed for the treatment of human patients with the anticoagulant drug
warfarin (Kangelaris et al. 2009 ). Therapeutic areas in veterinary medicine most
likely to benefit from such an approach would involve drugs with a low therapeutic
index (ratio of toxic dose to effective dose) used in the treatment of intractable
disorders. Consequently, cancer therapeutics, seizure treatment and prevention, anaes-
thesia, pain management, and infectious disease are some of the areas likely to gain
from advances in veterinary pharmacogenomics. As these are areas of importance for
human pharmacogenomics, it is anticipated that advances in human, veterinary and
comparative pharmacogenomics will be mutually beneficial.
References
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Aleman M, Brosnan RJ, Williams DC, LeCouteur RA, Imai A, Tharp BR, Steffey EP (2005)
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70 C.M. Mosher and M.H. Court