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In vitro characterization of the human cytochrome P‐450 involved in polymorphic oxidation of propafenone
Author(s) -
Kroemer Heyo K,
Mikus Gerd,
Kronbach Thomas,
Meyer Urs A,
Eichelbaum Michel
Publication year - 1989
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1989.5
Subject(s) - hydroxylation , propafenone , microsome , pharmacology , chemistry , cytochrome p450 , sparteine , cytochrome , cyp3a4 , biochemistry , isozyme , in vivo , debrisoquine , stereochemistry , in vitro , metabolism , biology , cyp2d6 , enzyme , medicine , genetics , atrial fibrillation
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‐450 db1 , 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 β‐adrenergic antagonist bufuralol. The l'hydroxylation of bufuralol is catalyzed by the P‐450 db1 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‐450 db1 , 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. Clinical Pharmacology and Therapeutics (1989) 45, 28–33; doi: 10.1038/clpt.1989.5