Oxidation of quinidine by human liver cytochrome P-450.
The anti-arrhythmic quinidine has been reported to be a competitive inhibitor of the catalytic activities of human liver P-450DB, including sparteine delta 2-oxidation and bufuralol 1'-hydroxylation, and we confirmed the observation that submicromolar concentrations are strongly inhibitory. Human liver microsomes oxidize quinidine to the 3-hydroxy (Km 4 microM) and N-oxide (Km 33 microM) products, consonant with in vivo observations. Both bufuralol and sparteine inhibited microsomal quinidine 3-hydroxylation. Liver microsomes prepared from DA strain rats showed a relative deficiency in quinidine 3-hydroxylase activity in females compared to males. These observations might suggest that quinidine oxidation is catalyzed by the same P-450 forms that oxidize debrisoquine, bufuralol, and sparteine; i.e., rat P-450UT-H and P-450DB. However, neither of these two purified enzymes catalyzed quinidine 3-hydroxylation, and anti-P-450UT-H, which strongly inhibits human liver microsomal bufuralol 1'-hydroxylation, did not substantially inhibit quinidine 3-hydroxylation or N-oxygenation. P-450MP, the human S-mephenytoin 4-hydroxylase, also does not appear to oxidize quinidine but P-450NF, the human nifedipine oxidase, does. Anti-P-450NF inhibited greater than 95% of the 3-hydroxylation and greater than 85% of the N-oxygenation of quinidine in several microsomal samples. Quinidine inhibited microsomal nifedipine oxidation and, in a series of human liver samples, rates of nifedipine oxidation were correlated with rates of quinidine oxidation. Thus, quinidine oxidation appears to be catalyzed primarily by P-450NF and not by P-450DB. Quinidine binds 2 orders of magnitude more tightly to P-450DB, which does not oxidize it, than to P-450NF, the major enzyme involved in its oxidation. The substrate specificity of human P-450NF is discussed further in terms of its regioselective oxidations of complex molecules including quinidine, aldrin, benzphetamine, cortisol, testosterone and androstenedione, estradiol, and several 2,6-dimethyl-1,4-dihydropyridines.
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009543:Nifedipine / Q000378:metabolism; D010084:Oxidation-Reduction; D011802:Quinidine / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
D004983:Ethanolamines; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine; D011802:Quinidine