Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations.
A number of human cytochrome P450 (CYP) isozymes have been shown to be genetically polymorphic, and extensive pharmaceutical studies have been conducted to characterize the clinical relevance of the polymorphism. Although the beagle is extensively used in the safety assessment studies of new drug candidates and agricultural chemicals, only a limited number of studies have been reported on the significance of the CYP isozyme polymorphism in dogs. Recently, a single nucleotide polymorphism that results in a deficiency of canine CYP1A2 was discovered. This deficiency was shown to significantly alter the pharmacokinetic behavior of two drugs, and can be associated with a large inter-individual difference in the kinetic behavior of a third. In this article, the five genetically polymorphic canine CYP isozymes that have been reported so far are reviewed, and the altered pharmacokinetics of the drugs concerned are described. Although little information on toxicological relevance has been reported, it is possible that the modified pharmacokinetics may also cause altered toxic responses as well. This phenomenon may occur only with the types of chemicals that are eliminated mainly through polymorphic-enzyme mediated metabolism. However, it is recommended that genetically pure beagles are used for the toxicity studies and safety assessment of new chemical entities in order to reduce the potential inter-individual differences.
Kamimura
H
H
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Azusawa 1-1-8, Itabashi-ku, Tokyo, Japan. hidetaka.kamimura@jp.astellas.com
D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004285:Dogs / Q000378:metabolism*; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic; D018675:Toxicity Tests
D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2