评估稳定型动脉粥样硬化性心血管疾病患者细胞色素 P450 衍生的类二十烷酸。
Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease.
机构信息
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
出版信息
Atherosclerosis. 2012 Jun;222(2):530-6. doi: 10.1016/j.atherosclerosis.2012.03.022. Epub 2012 Mar 27.
OBJECTIVE
Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD.
METHODS
Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression.
RESULTS
Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS).
CONCLUSIONS
Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.
目的
临床前和遗传流行病学研究表明，调节细胞色素 P450（CYP）介导的花生四烯酸代谢可能在冠心病（CAD）的治疗中有一定作用。然而，目前尚未评估 CAD 患者 CYP 衍生类二十烷酸代谢物个体间差异的预测因子。因此，首要目标是确定影响已确诊 CAD 患者 CYP 环氧合酶、可溶性环氧化物水解酶（sEH）和 CYP ω-羟化酶代谢的临床因素。
方法
采用 HPLC-MS/MS 法对 82 例稳定型、经血管造影证实的 CAD 患者和 36 例当地社区健康志愿者的血浆中环氧化二十碳三烯酸（EETs）、二羟二十碳三烯酸（DHETs）和 20-羟二十碳四烯酸（20-HETE）水平进行定量。采用回归分析评估 CYP 环氧合酶、sEH 和 CYP ω-羟化酶代谢功能的预测因子。
结果
肥胖与血浆 EET 水平和 14,15-EET：14,15-DHET 比值降低显著相关。年龄、糖尿病和吸烟也与 CYP 环氧合酶和 sEH 代谢活性显著相关，而仅肾素-血管紧张素系统抑制剂的使用与 CYP ω-羟化酶代谢活性相关。与健康志愿者相比，肥胖和非肥胖 CAD 患者的血浆 EETs（P<0.01）和环氧：二醇比值（P<0.01）均显著升高，而 20-HETE 水平无差异（P=NS）。
结论
这些发现表明，CYP 介导的类二十烷酸代谢在某些 CAD 患者亚群中失调，并表明与健康个体相比，稳定 CAD 患者的 CYP 环氧合酶和 sEH 代谢标志物，但不是 CYP ω-羟化酶代谢标志物发生改变。需要进一步研究以确定调节这些途径在 CAD 患者中的治疗作用。
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