动脉平滑肌中11,12-环氧二十碳三烯酸代谢新途径的功能意义。,Circulation Research

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动脉平滑肌中11,12-环氧二十碳三烯酸代谢新途径的功能意义。
Circulation Research ( IF 16.5 ) Pub Date : 1996-10-01 , DOI: 10.1161/01.res.79.4.784
X Fang ₁ , T L Kaduce , N L Weintraub , M VanRollins , A A Spector

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环氧二十碳三烯酸（EET）是衍生自花生四烯酸的细胞色素P-450代谢的有效血管扩张剂。已提出将EET快速转化为其相应的二羟基二十碳三烯酸（DHET）作为使EET具有生物惰性的方法。然而，尚未广泛研究EET的血管代谢和EET代谢产物的血管活性。因此，在猪主动脉平滑肌细胞中表征了11,12-EET代谢。细胞将[3H] 11,12-EET转化为11,12-DHET，并转化为新近鉴定的代谢物7,8-二羟基-十六碳二烯酸（DHHD）。培养基中11,12-DHET的积累在2至4小时内达到最大值，然后下降，而7,8-DHHD的积累连续增加并在8小时后超过11,12-DHET的量。[3H] 11，在未标记的11,12-DHET存在下，从12-EET到放射性标记的7,8-DHHD的转化减少，表明11,12-DHET是将11,12-EET转化为7,8-DHHD的中间体。这与通过环氧水解酶将11，12-EET转化为11，12-DHET的途径一致，该途径随后经历两次β-氧化形成7,8-DHHD。在用血栓烷模拟物收缩的猪冠状动脉环中，11,12-DHET产生的弛豫与11,12-EET产生的弛豫相似（分别在5μmol/ L时分别为77％和64％弛豫）。7,8-DHHD也产生血管舒张。因此，通过转化成11，12-DHET和7，8-DHHD不能消除11，12-EET的血管活性。这些结果表明11,12-DHET及其代谢物7,8-DHHD

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Functional implications of a newly characterized pathway of 11,12-epoxyeicosatrienoic acid metabolism in arterial smooth muscle.

Epoxyeicosatrienoic acids (EETs) are potent vasodilators derived from cytochrome P-450 metabolism of arachidonic acid. The rapid conversion of EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) has been proposed as a process whereby EETs are rendered biologically inactive. However, the vascular metabolism of EETs and the vasoactivities of EET metabolites have not been extensively studied. Accordingly, 11,12-EET metabolism was characterized in porcine aortic smooth muscle cells. The cells converted [3H]11,12-EET to 11,12-DHET and to a newly identified metabolite, 7,8-dihydroxy-hexadecadienoic acid (DHHD). 11,12-DHET accumulation in the medium reached a maximum in 2 to 4 hours and then declined, whereas 7,8-DHHD accumulation increased continuously and exceeded the amount of 11,12-DHET by 8 hours. [3H]11,12-EET conversion to radiolabeled 7,8-DHHD was reduced in the presence of unlabeled 11,12-DHET, indicating that 11,12-DHET is an intermediate in the conversion of 11,12-EET to 7,8-DHHD. This is consistent with a pathway whereby 11,12-EET is converted by an epoxide hydrolase to 11,12-DHET, which then undergoes two beta-oxidations to form 7,8-DHHD. In porcine coronary artery rings contracted with a thromboxane mimetic, 11,12-DHET produced relaxation similar in magnitude to that produced by 11,12-EET (77% versus 64% relaxation at 5 mumol/L, respectively). 7,8-DHHD also produced vasorelaxation. Thus, the vasoactivity of 11,12-EET is not eliminated by conversion to 11,12-DHET and 7,8-DHHD. These results suggest that 11,12-DHET and its metabolite, 7,8-DHHD, may contribute to the regulation of vascular tone in the porcine coronary artery and possibly other vascular tissues.

更新日期：2019-11-01

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