Oxidation of quinidine by human liver cytochrome P-450.
Oxidation of quinidine by human liver cytochrome P-450.
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发表时间：
1986-09
影响因子：
3.6
通讯作者：
F. Guengerich;D. Müller-Enoch;I. Blair
中科院分区：
文献类型：
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作者：
F. Guengerich;D. Müller-Enoch;I. Blair
据报道，抗心律失常奎尼丁是人肝脏 P-450DB 催化活性的竞争性抑制剂，包括金雀花 δ 2-氧化和丁呋洛尔 1'-羟基化，我们证实了亚微摩尔浓度具有强烈抑制作用的观察结果。人肝微粒体将奎尼丁氧化为 3-羟基 (Km 4 microM) 和 N-氧化物 (Km 33 microM) 产物，与体内观察结果一致。布呋洛尔和金雀花碱均抑制微粒体奎尼丁 3-羟基化。从 DA 品系大鼠制备的肝微粒体显示，与雄性相比，雌性大鼠的奎尼丁 3-羟化酶活性相对缺乏。这些观察结果可能表明，奎尼丁氧化是由与氧化异喹啉、丁呋洛尔和金雀花碱相同的 P-450 形式催化的；即，大鼠 P-450UT-H 和 P-450DB。然而，这两种纯化的酶均不催化奎尼丁3-羟基化，而抗P-450UT-H强烈抑制人肝微粒体布呋洛尔1'-羟基化，但基本上不抑制奎尼丁3-羟基化或N-氧合。 P-450MP（人 S-美芬妥英 4-羟化酶）似乎也不会氧化奎尼丁，但 P-450NF（人硝苯地平氧化酶）却可以。在一些微粒体样品中，抗 P-450NF 抑制奎尼丁超过 95% 的 3-羟基化和超过 85% 的 N-氧化。奎尼丁抑制微粒体硝苯地平氧化，在一系列人类肝脏样本中，硝苯地平氧化速率与奎尼丁氧化速率相关。因此，奎尼丁氧化似乎主要由 P-450NF 而非 P-450DB 催化。奎尼丁与 P-450DB 的结合比与参与其氧化的主要酶 P-450NF 的结合紧密 2 个数量级，而 P-450DB 不会氧化奎尼丁。人 P-450NF 的底物特异性进一步讨论了复杂分子的区域选择性氧化，包括奎尼丁、艾氏剂、苯丙胺、皮质醇、睾酮和雄烯二酮、雌二醇和几种 2,6-二甲基-1,4-二氢吡啶。
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.