Oxidation of indole by cytochrome P450 enzymes
Oxidation of indole by cytochrome P450 enzymes
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DOI：
10.1021/bi001229u
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发表时间：
2000-11-14
期刊：
影响因子：
2.9
通讯作者：
Guengerich, FP
中科院分区：
文献类型：
--
作者：
Gillam, EMJ;Notley, LM;Guengerich, FP
吲哚是肠道细菌色氨酸催化剂的产物，并被大量吸收到体内。已知该化合物被氧化为吲哚酚，并以吲哚酚（3-羟基吲哚）硫酸盐的形式经尿液排泄。吲哚酚进一步氧化和二聚导致靛蓝色素的形成。我们报告的明确识别的色素靛蓝和靛玉红作为产品的人细胞色素P450（P450）催化代谢的吲哚可见，H-1 NMR和质谱。P450 2A 6在这两种色素的形成中最活跃，其次是P450 2C 19和2 E1。通过HPLC/UV和质谱法表征吲哚代谢的其他产物。观察到吲哚酚（3-羟基吲哚）是P450 2A 6介导的代谢的瞬时产物;靛红、6-羟基吲哚和二氧吲哚在低水平下蓄积。羟吲哚是由P450 2A 6、2 E1和2C 19形成的主要产物，并且没有进一步转化。通过紫外光谱、核磁共振氢谱和质谱分析，确定了产物的结构为6 H-恶唑并[3，2-n：4，5-b ']二吲哚，并证明P450能催化吲哚氧化偶联形成二聚体。在此基础上，我们提出P450/NADPH-P450还原酶体系能催化吲哚氧化生成多种产物。
Indole is a product of tryptophan catabolism by gut bacteria and is absorbed into the body in substantial amounts. The compound is known to be oxidized to indoxyl and excreted in urine as indoxyl (3-hydroxyindole) sulfate. Further oxidation and dimerization of indoxyl leads to the formation of indigoid pigments. We report the definitive identification of the pigments indigo and indirubin as products of human cytochrome P450 (P450)-catalyzed metabolism of indole by visible, H-1 NMR, and mass spectrometry. P450 2A6 was most active in the formation of these two pigments, followed by P450s 2C19 and 2E1. Additional products of indole metabolism were characterized by HPLC/UV and mass spectrometry. Indoxyl (3-hydroxyindole) was observed as a transient product of P450 2A6-mediated metabolism; isatin, 6-hydroxyindole, and dioxindole accumulated at low levels. Oxindole was the predominant product formed by P450s 2A6, 2E1, and 2C19 and was not transformed further. A stable end product was assigned the structure 6H-oxazolo[3,2-n:4,5-b']diindole by UV, H-1 NMR, and mass spectrometry, and we conclude that P450s can catalyze the oxidative coupling of indoles to form this dimeric conjugate, On the basis of these results, we propose that the P450/NADPH-P450 reductase system can catalyze oxidation of indole to a variety of products.