Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides
Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides
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DOI：
10.1194/jlr.m300463-jlr200
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发表时间：
2004-08-01
影响因子：
6.5
通讯作者：
Salaün, JP
中科院分区：
文献类型：
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作者：
Le Quéré, V;Plée-Gautier, E;Salaün, JP
CYP4F 亚型参与重要细胞介质的氧化，例如白三烯 B-4 (LTB4) 和前列腺素。促炎剂 LTB4 和细胞毒性白细胞毒素与多种炎症性疾病有关。我们提供的证据表明，Z9(10)-环氧十八烷酸、Z9(10)-环氧十八烷-Z12-烯酸和Z12(13)-环氧十八烷-Z9-烯酸以及来自花生四烯酸[环氧二十碳三烯酸(EET)]的单环氧化物的羟基化对于调节 白细胞毒素和 EET 活性。这三种来自 C18 家族的环氧化衍生物（C18-环氧化物）被人肝微粒体转化为 18-羟基-C18-环氧化物，表观 K 值在 27.6 至 175 muM 之间。在重组 P450 酶中，CYP4F2 和 CYP4F3B 主要催化 C18 环氧化物的 omega-羟基化，表观 V-max 为 0.84 至 15.0 min(-1)，而 CYP4F3A（白细胞中发现的同种型）显示的表观 V-max 范围为 3.0 至 21.2 分钟(-1)。实验发现CYP4A11 的omega-羟基化速率在0.3 至2.7 分钟(-1) 之间。 CYP4F2和CYP4F3表现出对Z8(9)-EET的omega-羟基化的偏好，而人肝微粒体偏好Z11(12)-EET，并且在较小程度上偏好Z8(9)-EET。此外，来自 C18 环氧化物和 EET 的邻位二醇均被肝微粒体以及 CYP4F2 和 CYP4F3 进行 omega-羟基化。这些数据支持人类 CYP4F 亚家族参与脂肪酸环氧化物的 omega-羟基化的假设。这些发现表明，除了转化为邻位二醇或通过 β-氧化缩短链之外，还存在另一种途径可以使脂肪酸环氧化物失活。-Le Quere, V.、E. Plee-Gautier、P. Potin、S. Madec 和 J-P。萨朗。人类 CYP4F3 是脂肪酸环氧化物氧化的主要催化剂。
CYP4F isoforms are involved in the oxidation of important cellular mediators such as leukotriene B-4 (LTB4) and Prostaglandins. The proinflammatory agent LTB4 and cytotoxic leukotoxins have been associated with several inflammatory diseases. We present evidence that the hydroxylation of Z9(10)-epoxyoctadecanoic, Z9(10)-epoxyoctadec-Z12-enoic, and Z12(13)-epoxyoctadec-Z9-enoic acids and that of monoepoxides from arachidonic acid [epoxyeicosatrienoic acid (EET)] is important in the regulation of leukotoxin and EET activity. These three epoxidized derivatives from the C18 family (C18-epoxides) were converted to 18-hydroxy-C18-epoxides by human hepatic microsomes with apparent K. values of between 27.6 and 175 muM. Among recombinant P450 enzymes, CYP4F2 and CYP4F3B catalyzed mainly the omega-hydroxylation of C18-epoxides with an apparent V-max of between 0.84 and 15.0 min(-1), whereas the apparent V-max displayed by CYP4F3A, the isoform found in leukocytes, ranged from 3.0 to 21.2 min(-1). The rate of omega-hydroxylation by CYP4A11 was experimentally found to be between 0.3 and 2.7 min(-1). CYP4F2 and CYP4F3 exhibited preferences for omega-hydroxylation of Z8(9)-EET, whereas human liver microsomes preferred Z11(12)-EET and, to a lesser extent, Z8(9)-EET. Moreover, vicinal diol from both C18-epoxides and EETs were omega-hydroxylated by liver microsomes and by CYP4F2 and CYP4F3. These data support the hypothesis that the human CYP4F subfamily is involved in the omega-hydroxylation of fatty acid epoxides. These findings demonstrate that another pathway besides conversion to vicinal diol or chain shortening by beta-oxidation exists for fatty acid epoxide inactivation.-Le Quere, V., E. Plee-Gautier, P. Potin, S. Madec, and J-P. Salaun. Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides.