title: CYP2D-related metabolism in animals of the Canoidea superfamily - species differences.
abstract: CYP2D-related drug metabolism in liver microsomes from animals of the Canoidea super family, i.e. mink (Mustela vison), bears (Ursus arctos), foxes (Vulpes vulpes) and dogs, were investigated. Propranolol, bunitrolol and imipramine, which are typically substrates of CYP2D subfamilies, were used in the experiment. All the animals of the Canoidea superfamily that were tested lacked the ability to catalyse 7-hydroxylation of propranolol, which is one of the major metabolic pathways in rats. Stereoselectivity of propranolol metabolism was towards (S)-propranolol in all the reactions of the animals tested with the exception of mink, which showed a selective tendency towards (R)-propranolol in N-dealkylation. As far as metabolic patterns of (R)- and (S)-propranolol are concerned, bears, foxes and dogs are alike, but minks are somewhat different. Liver microsomes from mink showed, among the animals of the Canoidea superfamily, the lowest propranolol hydroxylase activity at 4- and 5-positions and imipramine 2-hydroxylation and {N-}demethylation activities. We could not detect bunitrolol 4-hydroxylation in mink liver microsomes at the low substrate concentration used. We conclude that mink have the lowest activity of CYP2D-related xenobiotic metabolism among the Canoidea superfamily.
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishizuka
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Masuda
authors.forename: F
authors.initials: F
authors.lastname: Akahori
authors.forename: A
authors.initials: A
authors.lastname: Kazusaka
authors.forename: S
authors.initials: S
authors.lastname: Fujita
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D046028:Canidae / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D005589:Foxes; D006900:Hydroxylation; D007099:Imipramine / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008907:Mink; D011412:Propanolamines / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013237:Stereoisomerism; D001503:Ursidae
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D007527:Isoenzymes; D011412:Propanolamines; D026361:Reactive Nitrogen Species; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; C084811:bunitrolol; D007099:Imipramine