title: In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone.
abstract: Propafenone is a new class 1 antiarrhythmic agent. The drug is extensively metabolized. 5-Hydroxylation and N-dealkylation constitute major metabolic pathways. Recently it has been demonstrated that the in vivo metabolism of propafenone is controlled by the debrisoquin/sparteine polymorphism. To elucidate which of the above metabolic reactions is catalyzed by cytochrome P-450db1, the formation of 5-hydroxypropafenone and N-desalkylpropafenone was studied in the microsomal fraction of four human kidney donor livers previously characterized with regard to their ability to hydroxylate the beta-adrenergic antagonist bufuralol. The l'hydroxylation of bufuralol is catalyzed by the P-450db1 responsible for polymorphic debrisoquin/sparteine oxidation. The formation of 5-hydroxypropafenone but not N-desalkylpropafenone was closely related to bufuralol l'hydroxylation. Incubation with LKM1 antibodies, which selectively recognize P-450db1, inhibited 5-hydroxypropafenone formation completely whereas N-dealkylation was unimpaired. Propafenone was a strong competitive inhibitor of bufuralol l'hydroxylation. Thus it can be concluded that 5-hydroxypropafenone is formed by the cytochrome P-450 isozyme involved in polymorphic bufuralol oxidation.
authors.affiliation: Dr. Margarete-Fischer-Bosch Institut für Klinische Pharmakologie, Stuttgart, Federal Republic of Germany.
authors.forename: H K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: G
authors.initials: G
authors.lastname: Mikus
authors.forename: T
authors.initials: T
authors.lastname: Kronbach
authors.forename: U A
authors.initials: UA
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003640:Dealkylation; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D011110:Polymorphism, Genetic; D011405:Propafenone / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D001323:Autoantibodies; D004983:Ethanolamines; D011405:Propafenone; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System