Stoltz R A, Conners M S, Dunn M W, Schwartzman M L
Department of Pharmacology, New York Medical College, Valhalla.
J Ocul Pharmacol. 1994 Spring;10(1):307-17. doi: 10.1089/jop.1994.10.307.
The corneal epithelium of several species, has the capacity to metabolize arachidonic acid (arachidonic acid) via an NADPH-dependent cytochrome P450 mechanism. The major metabolites are 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), both of which exist in stereoisomeric configurations. However, the R enantiomers are predominantly produced by this enzyme system and exhibit potent biological activities. 12(R)-HETE inhibits Na-K-ATPase, increases corneal thickness and reduces intraocular pressure. 12(R)-HETrE causes vasodilation, neutrophil chemoattraction and angiogenesis. The formation of these metabolites is unaffected by cyclooxygenase and lipoxygenase inhibitors (indomethacin, diclofenac and BW755C) but inhibited by cytochrome P450 enzyme inhibitors such as carbon monoxide, SKF-525A and clotrimazole. The capacity of the normal corneal epithelium to metabolize arachidonic acid via cytochrome P450 is very low although under certain conditions this enzymatic pathway may become greatly induced. Corneal epithelial hypoxia in response to contact lens wear results in the time-dependent formation of NADPH-cytochrome P450-dependent arachidonate metabolites, 12(R)-HETE and 12(R)-HETrE. Under this condition, metabolite production correlates strongly with the in situ inflammatory response and inhibition of their formation significantly attenuates inflammation. It is evident that the cytochrome P450 arachidonate metabolites should be added to the realm of cyclooxygenase and lipoxygenase-derived eicosanoids as possible inflammatory mediators. Therefore, studies to evaluate eicosanoid involvement in inflammation should examine inhibitors of this pathway in addition to the classically studied non-steroidal antiinflammatory drugs (NSAIDs).
几种物种的角膜上皮细胞能够通过一种依赖NADPH的细胞色素P450机制代谢花生四烯酸。主要代谢产物是12-羟基-5,8,10,14-二十碳四烯酸（12-HETE）和12-羟基-5,8,14-二十碳三烯酸（12-HETrE），两者都以立体异构形式存在。然而，R对映体主要由该酶系统产生并表现出强大的生物活性。12（R）-HETE抑制钠钾ATP酶，增加角膜厚度并降低眼压。12（R）-HETrE引起血管舒张、中性粒细胞趋化和血管生成。这些代谢产物的形成不受环氧化酶和脂氧化酶抑制剂（吲哚美辛、双氯芬酸和BW755C）的影响，但受到细胞色素P450酶抑制剂如一氧化碳、SKF-525A和克霉唑的抑制。正常角膜上皮细胞通过细胞色素P450代谢花生四烯酸的能力非常低，尽管在某些条件下这种酶促途径可能会被极大地诱导。佩戴隐形眼镜导致的角膜上皮缺氧会导致依赖NADPH-细胞色素P450的花生四烯酸代谢产物12（R）-HETE和12（R）-HETrE随时间形成。在这种情况下，代谢产物的产生与原位炎症反应密切相关，抑制它们的形成会显著减轻炎症。很明显，细胞色素P450花生四烯酸代谢产物应作为可能的炎症介质加入到环氧化酶和脂氧化酶衍生的类二十烷酸领域。因此，评估类二十烷酸参与炎症的研究除了经典研究的非甾体抗炎药（NSAIDs）外，还应检查该途径的抑制剂。
