FURAFYLLINE IS A POTENT AND SELECTIVE INHIBITOR OF CYTOCHROME-P450IA2 IN MAN
FURAFYLLINE IS A POTENT AND SELECTIVE INHIBITOR OF CYTOCHROME-P450IA2 IN MAN
复制标题
DOI：
10.1111/j.1365-2125.1990.tb03686.x
复制
发表时间：
1990-06-01
影响因子：
3.4
通讯作者：
DAVIES, DS
中科院分区：
文献类型：
--
作者：
SESARDIC, D;BOOBIS, AR;DAVIES, DS
1呋喃茶碱（1，8-二甲基-3-（2“-糠基）甲基黄嘌呤）是一种甲基黄嘌呤衍生物，在哮喘治疗中作为茶碱的长效替代品引入。呋拉茶碱给药与血浆咖啡因水平升高相关，这是由于抑制咖啡因氧化，这是一种由一种或多种烃诱导的P450同工酶催化的反应。我们现在已经研究了呋拉茶碱抑制人单氧化酶活性的选择性。2呋拉茶碱是人肝微粒体组分的高亲和力非那西丁O-脱乙基酶活性的有效的非竞争性抑制剂，该反应由P450 IA 2催化，IC 50值为0.07 μ m。3呋拉茶碱对P450其它同工酶（P450 IID 1、P450 IIC、P450 IIIA）催化的人单加氧酶活性影响很小或没有影响。特别令人感兴趣的是，呋拉茶碱没有抑制P450 IA 1，从芳烃羟化酶活性的评估，胎盘样本吸烟的妇女。结论：呋拉茶碱是一种高选择性的P450 IA 2抑制剂。5呋拉茶碱是咖啡因N3-去甲基化的有效抑制剂，也是N1-和N7-去甲基化的一个组分。这证实了早期的建议，咖啡因是一种选择性底物的烃诱导同工酶的P450在人，并确定这是P450 IA 2。因此，咖啡因N3-去甲基化应该提供了一个很好的测量P450 IA 2在人体内的活性。6虽然呋拉茶碱选择性抑制P450 IA 2，相对于P450 IA 1，在大鼠中，这是在1000倍的浓度所需的抑制人类同工酶，这表明一个主要的差异，在活性位点的几何形状之间的人类和大鼠的P450 IA 2的直系同源物。
1 Furafylline (1,8-dimethyl-3-(2''-furfuryl)methylxanthine) is a methylxanthine derivative that was introduced as a long-acting replacement for theophylline in the treatment of asthma. Administration of furafylline was associated with an elevation in plasma levels of caffeine, due to inhibition of caffeine oxidation, a reaction catalysed by one or more hydrocarbon-inducible isoenzymes of P450. We have now investigated the selectivity of inhibition of human monooyxgenase activities by furafylline. 2 Furafylline was a potent, non-competitive inhibitor of high affinity phenacetin O-deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 .mu.m. 3 Furafylline had either very little or no effect on human monooxygenase activities catalysed by other isoenzymes of P450, including P450IID1, P450IIC, P450IIIA. Of particular interest, furafylline did not inhibit P450IA1, assessed from aryl hydrocarbon hydroxylase activity of placental samples from women who smoked cigarettes. 4 It is concluded that furafylline is a highly selective inhibitor of P450IA2 in man. 5 Furafylline was a potent inhibitor of the N3-demethylation of caffeine and of a component of the N1- and N7-demethylation. This confirms earlier suggestions that caffeine is a selective substrate of a hydrocarbon-inducible isoenzyme of P450 in man, and identifies this as P450IA2. Thus, caffeine N3-demethylation should provide a good measure of the activity of P450IA2 in vivo in man. 6 Although furafylline selectively inhibited P450IA2, relative to P450IA1, in the rat, this was at 1000-times the concentration required to inhibit the human isoenzyme, suggesting a major difference in the active site geometry between the human and the rat orthologues of P450IA2.