Koley A P, Buters J T, Robinson R C, Markowitz A, Friedman F K
Laboratory of Molecular Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1997 Feb 7;272(6):3149-52. doi: 10.1074/jbc.272.6.3149.
The anticarcinogenicity of some flavonoids has been attributed to modulation of the cytochrome P450 enzymes, which metabolize procarcinogens to their activated forms. However, the mechanism by which flavonoids inhibit some P450-mediated activities while activating others is a longstanding, intriguing question. We employed flash photolysis to measure carbon monoxide binding to P450 as a rapid kinetic technique to probe the interaction of the prototype flavonoid alpha-naphthoflavone with human cytochrome P450s 1A1 and 3A4, whose benzo[a]pyrene hydroxylation activities are respectively inhibited and stimulated by this compound. This flavonoid inhibited P450 1A1 binding to benzo[a]pyrene via a classical competitive mechanism. In contrast, alpha-naphthoflavone stimulated P450 3A4 by selectively binding and activating an otherwise inactive subpopulation of this P450 and promoting benzo[a]pyrene binding to the latter. These data indicate that flavonoids enhance activity by increasing the pool of active P450 molecules within this P450 macrosystem. Activators in other biological systems may similarly exert their effect by expanding the population of active receptor molecules.
某些黄酮类化合物的抗癌性归因于对细胞色素P450酶的调节作用，该酶可将前致癌物代谢为其活性形式。然而，黄酮类化合物在抑制某些P450介导的活性的同时却激活另一些活性的机制，是一个长期存在的、引人关注的问题。我们采用闪光光解技术来测量一氧化碳与P450的结合，以此作为一种快速动力学技术，来探究原型黄酮α-萘黄酮与人类细胞色素P450 1A1和3A4的相互作用，该化合物对这两种酶的苯并[a]芘羟基化活性分别具有抑制和刺激作用。这种黄酮类化合物通过经典的竞争机制抑制P450 1A1与苯并[a]芘的结合。相反，α-萘黄酮通过选择性结合并激活P450 3A4中原本无活性的亚群，并促进苯并[a]芘与后者的结合，从而刺激P450 3A4。这些数据表明，黄酮类化合物通过增加该P450大系统内活性P450分子的数量来增强活性。其他生物系统中的激活剂可能同样通过增加活性受体分子的数量来发挥作用。
