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Cytochrome Genes Are Expressed in Dogs, Cats, and Pigs, and Encode Functional Drug-Metabolizing Enzymes. | LitMetric

Cytochrome Genes Are Expressed in Dogs, Cats, and Pigs, and Encode Functional Drug-Metabolizing Enzymes.

Drug Metab Dispos

Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (Y.U., M.Ij., O.Y., M.S., A.A.); Showa Pharmaceutical University, Machida, Japan (N.M., H.Y.); School of Veterinary Medicine, Kitasato University, Towadashi, Japan (H.K.); School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan (H.T.); Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan (H.M., S.M.M.N., Y.I., M.Is.); and Graduate School of Agriculture, Ehime University, Matsuyama, Japan (H.M.)

Published: November 2022

AI Article Synopsis

  • The study identifies and characterizes seven cytochrome P450 (CYP) enzymes in dogs, cats, and pigs that are homologous to human CYP2J2, crucial for drug metabolism in both human and veterinary medicine.* -
  • These enzymes, particularly dog CYP2J2 and pig CYP2J34 and CYP2J35, were found to metabolize specific drugs similarly to human CYP2J2, indicating their potential functional relevance in drug therapy.* -
  • Phylogenetic analysis shows that dog and cat CYP2J2s are closely related, while pig CYP2Js form a distinct cluster, and all CYP2Js exhibit similar enzymatic behaviors but with slight variations in drug oxidation capabilities.*

Article Abstract

Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven genes contain nine coding exons and are located in corresponding genomic regions, with the pig genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in the small intestine with additional expression in the kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocityversus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. SIGNIFICANCE STATEMENT: Dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in the small intestine, similar to human CYP2J2.

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Source
http://dx.doi.org/10.1124/dmd.122.000930DOI Listing

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