20-羟-二十烷四烯酸对血管内皮细胞的作用研究进展

20-羟-二十烷四烯酸(20-hydroxyeicosatetraenoic acid,20-HETE)是花生四烯酸的细胞色素P-450代谢途径的一个重要代谢产物。近年来研究发现20-HETE对血管内皮细胞发挥重要的生理和病理生理作用。20-HETE可激活内皮细胞烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleoti-de phosphate,NADPH)氧化酶系统和核因子-кB(nuclear factor-кB,NF-кB)通路发挥氧化应激和促炎作用;20-HETE可介导血管内皮细胞内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的解离、降低NO的生物利用度及诱导血管紧张素转换酶,调节血管的舒张和收缩功能;20-HETE还可促进内皮细胞的增生而促进血管新生。但国内对20-HETE研究甚少,因此本文对近年来国际上关于20-HETE对血管内皮细胞的研究作一综述。     

20-HETE在心血管疾病中的作用

20-羟二十四烷四烯酸(20-hydroxyeicosatetraenoic acid,20-HETE)在哺乳动物中由CYP4A酶和4F酶系催化花生四烯酸(arachidonic acid,AA)w-羟基代谢生成的产物之一。随着研究深入,人们发现20-HETE是一种有效的血管活性脂,它可以刺激血管平滑肌的收缩、迁移和增殖,并且能引起内皮功能障碍以及炎症反应。在心血管系统中,20-HETE具有很强的缩血管作用,与多种心血管疾病的发生发展密切相关,其水平的上调对于炎症反应、氧化应激以及内皮功能障碍都有着促进作用。本文就近年来20-HETE在心血管疾病中作用的研究做一简要综述。     

花生四烯酸细胞色素P450代谢途径在糖尿病中的作用研究进展

花生四烯酸(arachidonic acid,AA)是生物体内含量最丰富,其代谢产物最具生物活性的小分子物质之一.其代谢产物在众多生理及病理生理过程中发挥重要的调节作用.它们除参与细胞生长和分化、生殖和发育、体温及血压的维持等重要生理过程调节外,也在诸如炎症、疼痛、肿瘤、高血压、动脉粥样硬化等人类重大疾病的发生发展中发挥着极其重要的作用.AA及其代谢产物在糖尿病发生发展中的作用也逐渐引起关注,尤其是环氧化酶和脂氧酶代谢途径与糖尿病的关系研究较为广泛.花生四烯酸还可以经细胞色素P450途径产生表氧-二十碳三烯酸(EETs)和20-羟二十烷四烯酸(20-HETE).它们与糖尿病的关系研究甚少.近年来发现EETs和其水解酶与葡萄糖的吸收和胰岛素抵抗有关,20-HETE则参与糖尿病肾功能损伤和血管活性的改变.因而探讨花生四烯酸P450代谢途径对糖尿病的影响及其机制将有利于进一步阐明糖尿病的发病机理,为糖尿病的防治提出新的思路.本文就近五年有关花生四烯酸P450代谢途径与糖尿病关系的研究做一综述,以期为我国在该领域的研究提供新的方向.     

花生四烯酸的细胞色素P450酶代谢途径产物EETs和20-HETE在血管功能调控中的作用

花生四烯酸(arachidonic acids, AA)广泛存在于生物体内,并可通过多种途径代谢成为具有强大生物学功能的脂质小分子。其中,经细胞色素P450酶代谢途径产生的环氧二十碳三烯酸(epoxyeicosatrienoic acids, EETs)及20-羟基二十碳四烯酸(20-hydroxyeicosatetraenoic acid, 20-HETE)的作用备受关注,尤其是在血管稳态中的作用。血管功能调控是维持血管稳态的基础,主要通过对血管的结构和(或)生物学活性的影响而实现。近30年来,EETs及20-HETE在血管功能调控中的作用及机制被广泛研究。本文分别就EETs和20-HETE在血管新生和血管炎症反应等方面的研究进展逐一进行综述。总的来说,在生物学活性方面,EETs主要体现为舒张血管和抑制血管炎症,而20-HETE则可以促进血管收缩和血管炎症。两者在血管新生方面的作用类似,都可以促进血管新生。另外,本文还对EETs和20-HETE在常见的血管性疾病(如高血压和心肌缺血)中的作用进行了探讨,对其中的作用机制进行了分析和总结,并对基于EETs和20-HETE的血管性疾病靶向治疗提出了展望。     

Kv3.4通道参与15-羟二十碳四烯酸诱导的大鼠肺动脉收缩

通过组织浴槽血管环方法观察Kv3．4通道特异阻断剂BDS-Ⅰ对15-羟二十碳四烯酸（15-hydroxyeicosatetraenoic acid,15-FETE）收缩肺动脉血管的影响;通过酶法分离、培养Wistar大鼠肺动脉血管平滑肌细胞（pulmonary artery smooth musclecells,PASMCs）,RT-PCR和Western blot技术观察15-HETE对大鼠PASMCs上Kv3．4通道表达的影响,以探讨Kv3．4通道在15-HETE收缩肺动脉过程中的作用。结果如下：（1）15-HETE以浓度依赖方式使肺动脉环张力增加,对缺氧组大鼠肺动脉环张力作用更为明显,与正常对照组相比差异显著;（2）除去肺动脉内皮后,15-HETE引起血管收缩的强度较内皮完整时增强,呈剂量依赖性收缩反应;（3）阻断Kv3．4通道可抑制15-HETE收缩肺动脉;（4）15-HETE下调PASMCs膜上Kv3．4通道mRNA及蛋白质表达。上述观察结果提示Kv3．4通道参与由15-HETE引起的缺氧肺动脉血管收缩（hypoxic pulmonary vasoconstriction,HPV）。     

ERK1/2通路参与15-羟二十碳四烯酸收缩缺氧大鼠肺动脉的过程

缺氧诱导的15-羟二十碳四烯酸（15-hydroxyeicosatetraenoic acid,15-HETE）是引起肺动脉收缩的重要介导因子。15-HETE引起肺动脉收缩的信号转导途径尚不清楚。本研究旨在确定细胞外信号调节激酶1／2（extracellular signal-regulated kinase-1／2,ERK1／2）信号转导通路是否参与15-HETE收缩缺氧火鼠肺动脉的过程。采用组织浴槽肺动脉环张力检测、蛋白质免疫印迹Western blot）和免疫细胞化学方法。制备缺氧大鼠动物模型,成年雄性Wistar大鼠在低氧环境下（吸入氧分数为0．12）正常喂养9d。显微分离直径1-1．5mm肺动脉,剪成长为3mm的动脉环,进行血管张力检测。用ERK1／2上游激酶（MEK）抑制剂PD98059抑制ERK1／2活性。结果显示,PD98059可明显抑制15-HETE对缺氧大鼠肺动脉环的收缩作用。在去除内皮的肺动脉环,PD98059仍叮明显降低15-HETE的缩血管作用。Western blot和免疫细胞化学结果都显示,15-HETE能促进ERK1／2磷酸化。由此表明ERK1／2信号转导通路参与15-HETE收缩缺氧大鼠肺动脉的过程。     

15-羟二十碳四烯酸下调肺动脉内皮型一氧化氮合酶的活性

15-羟二十碳四烯酸（15-hydroxyeicosatetraenoic acid,15-HETE）在低氧性肺血管收缩中起着重要作用,低氧肺动脉高压下调内皮型。氧化氮合酶（endothelial nitric oxide synthase,eNOS）,使一氧化氮（nitric oxide,NO）的产量下降,但目前尚无关于15-HETE与eNOS／NO相互作用研究的报道。我们通过Wistar大鼠肺动脉环张力、牛肺动脉内皮细胞NO产量、总eNOS表达及eNOS磷酸化测定等方法对15-HETE与eNOS／NO的相互作用进行研究。首先分离人鼠肺动脉,分为eNOS抑制剂L-NAME组（0．1mmol／L）、去缸管内皮组与内皮完整组,用15-HETE作用夫鼠离体肺动脉环,测定肺动脉张力。结果表明,L-NAME组、去除内皮组与内皮完整组分别比较,15-HETE对血管的收缩作用增强,且都有统计学意义（P〈0．05）。培养牛肺动脉内皮细胞,分别用15-HETE、15-脂氧酶（15-lipoxygenase,15-LO）抑制剂[（cinnamyl 3,4-dihydroxy-[alpha]-cyanocinnamate,CDC）和（nordihydroguiairetic acid,YDGA）]处理细胞,通过Greiss方法检测亚硝酸盐含量,间接测定NO产量,与对照组比较,1μmol／L 15-HETE明显降低肺动脉内皮细胞NO水平（P〈0．05）,10μmol／L CDC和0．1mmol／L NDGA显著增加NO水平（分别是P〈0．05,P〈0．01）;通过Western blot检测不同时间（5,10,15,20,30,60min）eNOS的表达情况,结果显示,15-HETE的不同作用时间,没有引起eNOS表达的明显不同;用苏氨酸495位点磷酸化eNOS（Thr495）抗体进行免疫沉淀,再用总eNOS抗体和15-LO抗体通过Western blot检测磷酸化型含量,问接测定eNOS活性,结果表明15-HETE增强Thr495磷酸化型eNOS含量。由于Thr495为eNOS抑制性磷酸化位点,因此15-HETE降低eNOS活性。这些数据表明：15-HETE的缩血管作用有eNOS／NO参与,15-HETE可以通过磷酸化Thr495位点降低eNOS活性,并且首次发现磷酸化eNOS（Thr495）和15-LO之间存在蛋白质相互作用。     

15-脂氧合酶/15-羟廿碳四烯酸在缺氧性肺动脉高压中的作用和机制

肺动脉高压是一种病因复杂的罕见病,以肺动脉阻力增高,引起右心室后负荷增大,最终导致右心室功能衰竭而使患者死亡为特征。肺血管花生四烯酸信号通路异常在肺动脉高压中发挥重要作用。肺动脉高压患者肺动脉内皮细胞、平滑肌细胞和成纤维细胞中15-脂氧合酶(15-lipoxygenase, 15-LO)及其代谢产物15-羟廿碳四烯酸(15-hydroxyeicosatetraenoic acid,15-HETE)水平均升高。在缺氧条件下,15-LO/15-HETE引起肺动脉收缩,促进肺动脉内皮细胞和平滑肌细胞增殖,抑制肺动脉平滑肌细胞凋亡,促进肺血管外膜纤维化,进而导致肺动脉高压的发生。本文主要对15-LO/15-HETE与缺氧性肺动脉高压相关性的研究进行综述,以阐明15-LO/15-HETE在缺氧性肺动脉高压中发挥的核心作用。     

花生四烯酸Alox15/12-HETE代谢通路抑制血管钙化的发生

本研究旨在探索血管钙化中花生四烯酸脂氧酶代谢产物的变化及作用。采用5/6肾切除及高磷饲喂的方法建立小鼠血管钙化的模型。在造模6周后,检测主动脉全长血管钙含量,主动脉弓部进行茜素红染色和Von Kossa染色检测钙沉积情况。收集对照血管和钙化血管组织进行花生四烯酸代谢产物的质谱检测,分析脂氧酶通路代谢小分子的变化。通过实时定量PCR方法检测钙化血管脂氧酶的表达改变。使用脂氧酶抑制剂明确脂氧酶代谢通路对血管钙化的影响。结果显示,造模6周后,肾切除组小鼠血管钙含量比假手术组显著升高(P 0.05),茜素红染色和Von Kossa染色显示肾切除小鼠主动脉弓部有明显的钙沉积,表明小鼠血管钙化造模成功。收取造模6周的钙化血管和对照血管,通过液相色谱-质谱(LC-MS)方法检测到9种花生四烯酸脂氧酶代谢产物,多种代谢产物(12-HETE、11-HETE、15-HETE等)的含量在钙化血管中显著升高,其中12-HETE含量最高并且升高最显著。进一步检测钙化血管中产生12-HETE的代谢酶的mRNA水平,发现花生四烯酸脂氧酶15(arachidonate 15-lipoxygenase, Alox15)表达增加。Alox15特异性抑制剂PD146176可显著降低血浆12-HETE水平,促进主动脉弓部的钙沉积、增加血管钙含量。这些结果显示花生四烯酸脂氧酶代谢在钙化血管中活化,Alox15/12-HETE通路可能对血管钙化发挥保护作用。     

昆虫中的细胞色素P-450及其特性

<正> 细胞色素P-450在微粒体多功能氧化酶系(MFO)中起着关键性作用。它能与氧分子和底物结合,并参与氧的活化。因此,P-450在杀中剂代谢、昆虫的选择毒性和抗药性、在保幼激素和脱皮激素的代谢以及在昆虫对寄主植物的适应性中都有着极其重要的作用。 自50年代后期以来,人们不仅对P-450的分子性质、光谱性质和多样性进行了详细研究,而且对P-450与P-450-还原酶、磷脂的相互关系及其在膜中的结构也进行了研究。目前     

The role of 20-HETE in androgen-mediated hypertension

Androgen plays an important role in blood pressure regulation. Epidemiological studies have shown that men have a higher prevalence for developing hypertension than aged-matched, premenopausal women. Interestingly, postmenopausal women and women with polycystic ovary syndrome, both of which have increased endogenous androgen production, have elevated risks for hypertension suggesting that androgen may contribute to its development. Studies from our laboratory and others have provided substantial evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) mediates the hypertension seen in rodents treated with androgen. 20-HETE is the cytochrome P450 (CYP)-derived ω-hydroxylated metabolite of arachidonic acid. 20-HETE plays a complex role in blood pressure regulation. In the kidney tubules, 20-HETE decreases blood pressure by promoting natriuresis, while in the microvasculature it has a pressor effect. In the microcirculation, 20-HETE participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor stimuli and contributes to myogenic, mitogenic and angiogenic responses. In addition, 20-HETE acts on the endothelium to promote endothelial dysfunction and endothelial activation. Recently, we have demonstrated that 20-HETE induces endothelial ACE thus setting forth a potential feed forward mechanism through activation of the renin-angiotensin-aldosterone system. In this review, we will discuss the pro-hypertensive effects of 20-HETE and its role in androgen-induced vascular dysfunction and hypertension.     

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid omega-hydroxylase activity

The cytochrome P-450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 +/- 3.2 mmHg; P < 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.     

The stimulation of arachidonic acid metabolism in human platelets by hydrodynamic stresses

Even though shear-induced platelet activation and aggregation have been studied for about 20 years, there remains some controversy concerning the arachidonic acid metabolites formed during stress activation and the role of thromboxane A2 in shear-induced platelet aggregation. In this study, platelets were labelled with [1-14C]arachidonic acid to follow the metabolism of arachidonic acid in stimulated platelets using HPLC and scintillation counting. Platelets activated by thrombin formed principally thromboxane A2, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). In contrast, for platelets activated by shear--though arachidonic acid metabolism was stimulated--only 12-HETE was formed and essentially no cyclooxygenase metabolites were detected. This indicates that physical forces may initiate a different pathway for eicosanoid metabolism than most commonly used chemical stimuli and perhaps also implies that regulation of the cyclooxygenase activity may be a secondary level of regulation in eicosanoid metabolism.     

20-HETE in neovascularization

Cytochrome P450 4A/F (CYP4A/F) converts arachidonic acid (AA) to 20-HETE by ω-hydroxylation. The contribution of 20-HETE to the regulation of myogenic response, blood pressure, and mitogenic actions has been well summarized. This review focuses on the emerging role of 20-HETE in physiological and pathological vascularization. 20-HETE has been shown to regulate vascular smooth muscle cells (VSMC) and endothelial cells (EC) by affecting their proliferation, migration, survival, and tube formation. Furthermore, the proliferation, migration, secretion of proangiogenic molecules (such as HIF-1α, VEGF, SDF-1α), and tube formation of endothelial progenitor cells (EPC) are stimulated by 20-HETE. These effects are mediated through c-Src- and EGFR-mediated downstream signaling pathways, including MAPK and PI3K/Akt pathways, eNOS uncoupling, and NOX/ROS system activation. Therefore, the CYP4A/F-20-HETE system may be a therapeutic target for the treatment of abnormal angiogenic diseases.     

Detection of 20-hydroxyeicosatetraenoic acid in rat urine

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonate metabolite of the cytochrome P450 omega hydroxylase, was detected in rat urine by gas chromatography-mass spectrometric techniques. The concentration of 20-HETE in urine from 7-week-old hypertensive and normotensive rats was 2.1 and 1.3 nM, respectively. This is the first demonstration of 20-HETE urinary excretion and thus calls attention to the possibility that 20-HETE participates in the regulation of renal function via its effect on vascular tone and ion transport processes.     

20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid (AA) metabolite synthesized by cytochrome P-450 omega-oxidases, is reported to produce vasoconstriction in the cerebral circulation. However, we find that like 14,15-epoxyeicosatrienoic acid (14,15-EET), 20-HETE produces dilation of mouse basilar artery preconstricted with U-46619 in vitro. Indomethacin inhibited the vasodilation produced by 20-HETE but not by 14,15-EET, suggesting a cyclooxygenase (COX)-dependent mechanism. Metabolic studies indicated several mechanisms that may play a role in this process. Mouse brain endothelial cells (MBEC) converted 20-HETE to 20-OH-PGE(2), which was as potent as PGE(2) in dilating the basilar artery. 20-HETE also stimulated AA release and PGE(2) and 6-keto-PGF(1alpha) production in MBEC. Furthermore, the basilar artery converted 20-HETE to 20-COOH-AA, which also produced COX-dependent dilation of the basilar artery. 20-COOH-AA increased AA release and PGE(2) and 6-keto-PGF(1alpha) production by the MBEC, but to a lesser extent than 20-HETE. Whereas the conversion of 20-HETE to 20-OH-PGE(2) and production of endogenous prostaglandins probably are primarily responsible for vasodilation, the production of 20-COOH-AA also may contribute to this process.     

20-hydroxyeicosatetraenoic acid (20-HETE) metabolism in coronary endothelial cells

We have investigated the role of endothelial cells in the metabolism of 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoactive mediator synthesized from arachidonic acid by cytochrome P450 omega-oxidases. Porcine coronary artery endothelial cells (PCEC) incorporated 20-[(3)H]HETE primarily into the sn-2 position of phospholipids through a coenzyme A-dependent process. The incorporation was reduced by equimolar amounts of arachidonic, eicosapentaenoic or 8,9-epoxyeicosatrienoic acids, but some uptake persisted even when a 10-fold excess of arachidonic acid was available. The retention of 20-[(3)H]HETE increased substantially when methyl arachidonoyl fluorophosphonate, but not bromoenol lactone, was added, suggesting that a Ca(2+)-dependent cytosolic phospholipase A(2) released the 20-HETE contained in PCEC phospholipids. Addition of calcium ionophore A23187 produced a rapid release of 20-[(3)H]HETE from the PCEC, a finding that also is consistent with a Ca(2+)-dependent mobilization process. PCEC also converted 20-[(3)H]HETE to 20-carboxy-arachidonic acid (20-COOH-AA) and 18-, 16-, and 14-carbon beta-oxidation products. 20-COOH-AA produced vasodilation in porcine coronary arterioles, but 20-HETE was inactive. These results suggest that the incorporation of 20-HETE and its subsequent conversion to 20-COOH-AA in the endothelium may be important in modulating coronary vascular function.     

Effect of arachidonic acid on activity of the apical K+ channel in the thick ascending limb of the rat kidney

We have used patch-clamp techniques to study the effects of arachidonic acid (AA) on the activity of the 70-pS K+ channel, the predominant type of the two apical K+ channels operating under physiological conditions in the thick ascending limb (TAL) of the rat kidney. Addition of 5-10 microM AA blocked the activity of the 70-pS K+ channel in both cell- attached and inside-out patches. The inhibitory effect of AA was specific, because application of 10 microM linoleic acid, oleic acid, or palmitic acid failed to mimic the effect of AA. The effect of AA could not be blocked by pretreatment of the TAL tubules with either 5 microM indomethacin (inhibitor of cyclooxygenase) or 4 microM cinnamyl- 3,4-dihydroxy-alpha-cyanocinnamate (CDC) (inhibitor of lipooxygenase). In contrast, addition of 5 microM 17-octadecynoic acid (17-ODYA), an inhibitor of P450 monooxygenases, abolised the effect of AA on the channel activity, indicating that the effect was mediated by cytochrome P450 metabolites of AA. Addition of 10 nM 20-hydroxyeicosatetraenoic acid (20-HETE), the main metabolite of the cytochrome P450 metabolic pathway in the medullary TAL, mimicked the inhibitory effect of 10 microM AA. However, addition of 100 nM 19-HETE or 17-HETE had no significant effects and 100 nM 20-carboxy AA (20-COOH) reduced the channel activity by only 20%, indicating that the inhibitory effect of 20-HETE was specific and responsible for the action of AA. Inhibition of the P450 metabolic pathway by either 5 microM 17-ODYA or 12, 12- dibromododec-11-enoic acid (DBDD) dramatically increased the channel activity by 280% in cell-attached patches. The stimulatory effect of 17- ODYA or DBDD was not observed in inside-out patches. The results strongly indicate that 20-HETE is a specific inhibitor for the 70-pS K+ channel and may play an important role in the regulation of the K+ channel activity in the TAL.     

CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis induced by electrical stimulation in skeletal muscle. Less is known about the role of arachidonic acid metabolites in the control of growth of blood vessels in vivo. The present study examined the role of 20-hydroxyeicosatetraenoic acid (20-HETE) on the angiogenesis induced by electrical stimulation in skeletal muscle. The tibialis anterior and extensor digitorum longus muscles of rats were stimulated for 7 days. Electrical stimulation significantly increased the 20-HETE formation and angiogenesis in the muscles, which was blocked by chronic treatment with N-hydroxy-N'-(4-butyl-2-methylphenol)formamidine (HET0016) or 1-aminobenzotriazole (ABT). Chronic treatment with either HET0016 or ABT did not block the increases in VEGF protein expression in both muscles. To analyze the role of VEGF on 20-HETE formation, additional rats were treated with VEGF-neutralizing antibody (VEGF Ab). VEGF Ab blocked the increases of 20-HETE formation induced by stimulation. These results place 20-HETE in the downstream signaling pathway for angiogenesis and show that both VEGF and 20-HETE are involved in the angiogenesis induced by electrical stimulation in skeletal muscle.     

CYP4F3B is induced by PGA1 in human liver cells: a regulation of the 20-HETE synthesis

The regulation of the human liver-specific cytochrome P450 4F3B (CYP4F3B) isoform, a splice variant of the CYP4F3 gene with strong substrate specificity for long chain fatty acids, is yet an unsolved question. This report provides the first evidence that CYP4F3B is uniquely induced by prostaglandin A(1) (PGA(1)) in human hepatocyte-like HepaRG cells and leads to the synthesis of 20-hydroxy-eicosatetraenoic acids (HETEs). Real time PCR, immunoblot analysis with a specific antipeptide antibody, and determination of fatty acid omega-hydroxylase activity demonstrate that PGA(1) treatment strongly increases expression of CYP4F3B. This induction drives the production of 20-HETE (19-fold increase). SiRNA-mediated-silencing of CYP4F3 suppresses both 20-HETE synthesis and PGA(1) induced 20-HETE production. Taken together, these results provide evidence that CYP4F3B is the key enzyme to produce 20-HETE by omega-hydroxylation of arachidonic acid in liver cells. Since 20-HETE is a potent activator of PPARalpha and an important inflammatory mediator, CYP4F3B may exert important functions in lipid homeostasis and in inflammatory diseases.