CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy.
CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy.
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DOI：
10.2174/1568026611313120007
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发表时间：
2013-05
影响因子：
3.4
通讯作者：
Cheng Chen;Daowen Wang
中科院分区：
文献类型：
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作者：
Cheng Chen;Daowen Wang
花生四烯酸通过不同的酶系统转化为类花生酸介质：环氧合酶、脂氧合酶和细胞色素P450（P450）单加氧酶途径（ω/ω-羟基化酶和环氧合酶）。CYP 2 J2、CYP 2C 8和CYP 2C 9是在人的内皮、心肌和肾脏中大量表达的主要的环氧酶同工型。环氧合酶的主要环氧化产物是顺式环氧二十碳三烯酸（E3）的四种区域异构体：5，6-、8，9-、11，12-和14，15-E3。大量研究表明，环氧合酶和雌二醇的心血管保护作用范围从血管舒张、抗高血压、促血管生成、抗动脉粥样硬化和抗炎到抗缺血-再灌注引起的损伤。近年来，花生四烯酸及其代谢产物在肿瘤生物学中的作用引起了人们的广泛关注。然而，环氧合酶衍生的Escherichia coli和癌症却很少受到关注。研究表明，在人类肿瘤中，表氧合酶和雌二醇显著上调，并促进肿瘤进展和转移。此外，来自特非那定的CYP 2 J2特异性抑制剂在体外和体内均表现出较强的抗肿瘤活性。提示CYP 2 J2可能是治疗人类癌症的治疗靶点。
Arachidonic acids are converted to eicosanoid mediators by the distinct enzyme systems: cyclooxygenase, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways (ω/ω⁻¹-hydroxylases and epoxygenases). CYP2J2, CYP2C8 and CYP2C9 are the predominant epoxygenase isoforms abundantly expressed in the endothelium, myocardium, and kidney in human. The primary epoxidation products by epoxygenases are four regioisomers of cis-epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EETs. Numerous studies demonstrated that the cardiovascular protective effects of CYP epoxygenases and EETs range from vasodilation, anti-hypertension, pro-angiogenesis, anti-atherosclerosis, and anti-inflammation to anti-injury caused by ischemia-reperfusion. The roles of arachidonic acids and its metabolites in cancer biology have recently attracted great attentions. However, CYP epoxygenase derived EETs and cancer has received little attention. It was demonstrated that CYP epoxygenases and EETs are significantly upregulated in human tumors and promote tumor progression and metastasis. Additionally, specific inhibitors of CYP2J2, derived from terfenadine, exhibit strong anti-tumor activity in vitro and in vivo. It is implicated that CYP2J2 may be a therapeutic target for treating human cancers.