Kom Ghainsom D, Schwedhelm Edzard, Maas Renke, Schneider Lydia, Benndorf Ralf, Böger Rainer H
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Centre Hamburg--Eppendorf, Hamburg, Germany.
Br J Clin Pharmacol. 2007 Jun;63(6):672-9. doi: 10.1111/j.1365-2125.2006.02832.x. Epub 2007 Jan 3.
Isoprostanes are the product of free radical oxidation of arachidonic acid, whose hydrolysis from phospholipids is presumably catalysed by phospholipases A(2) (PLA(2)s) such as group IIA or V PLA(2)s, or group VII PLA(2)[platelet-activating factor acetylhydrolase (PAF-AH), lipoprotein-associated phospholipase]. Atorvastatin reduces concentrations of low-density lipoprotein (LDL), with which PAF-AH is associated, and PLA(2)s' protein concentrations. We investigated the effect of atorvastatin on PLA(2)s and PAF-AH activity and the urinary excretion of 15-F(2trans)-isoprostane (15-F(2t)-IsoP, 8-iso-PGF(2alpha), iPF(2alpha)-III).
Twenty-four hypercholesterolaemic individuals naive to lipid-lowering therapy were randomized to atorvastatin 40 mg or placebo for 6 weeks. The 15-F(2t)-isoP urinary excretion (gas chromatography/mass spectrometry), PAF-AH and group IIA and V PLA(2) activities (photometry) were assessed at baseline and end-point.
At end-point, 15-F(2t)-isoP urinary excretion concentrations as well as PLA(2)s' activity were unchanged under atorvastatin (mean change 0.21 +/- 1.79 ng h(-1), 95% confidence interval -0.92, 1.35 and 0.33 +/- 0.94 nmol min(-1) ml(-1), -0.27, 0.93) and under placebo (mean change 0.69 +/- 1.69 ng h(-1), -0.52, 1.90 and 1.29 +/- 2.16 nmol min(-1) ml(-1), -0.25, 2.84). Atorvastatin treatment decreased total (P < 0.001) and LDL-cholesterol (P < 0.001) but had no effect on high-density lipoprotein. PAF-AH activity was lowered in the atorvastatin group (mean change - 5.27+/- 1.96 nmol min(-1) ml(-1), -6.51, -4.03, P < 0.001) but not in the placebo group (mean change 1.02 +/- 1.64 nmol min(-1) ml(-1), 0.15, 2.20), and the change in PAF-AH activity was correlated with that in total (P = 0.03) and LDL-cholesterol (P = 0.03).
Our results show a lowering effect of atorvastatin on PAF-AH activity associated with its lipid-lowering effect and exclude a key role of PAF-AH in the liberation of 15-F(2t)-isoP from phospholipids.
异前列腺素是花生四烯酸自由基氧化的产物，其从磷脂的水解可能由磷脂酶A(2)（PLA(2)）催化，如IIA或V组PLA(2)，或VII组PLA(2)[血小板活化因子乙酰水解酶（PAF-AH），脂蛋白相关磷脂酶]。阿托伐他汀可降低与PAF-AH相关的低密度脂蛋白（LDL）浓度以及PLA(2)的蛋白质浓度。我们研究了阿托伐他汀对PLA(2)和PAF-AH活性以及15-F(2反式)-异前列腺素（15-F(2t)-IsoP，8-异-PGF(2α)，iPF(2α)-III）尿排泄的影响。
24名未接受过降脂治疗的高胆固醇血症患者被随机分为阿托伐他汀40mg组或安慰剂组，为期6周。在基线和终点时评估15-F(2t)-异前列腺素尿排泄（气相色谱/质谱法）、PAF-AH以及IIA和V组PLA(2)活性（光度法）。
在终点时，阿托伐他汀治疗组和安慰剂组的15-F(2t)-异前列腺素尿排泄浓度以及PLA(2)活性均未改变（阿托伐他汀组平均变化0.21±1.79ng h(-1)，95%置信区间-0.92，1.35；0.33±0.94nmol min(-1) ml(-1)，-0.27, 0.93；安慰剂组平均变化0.69±1.69ng h(-1)，-0.52，1.90；1.29±2.16nmol min(-1) ml(-1)，-0.25，2.84）。阿托伐他汀治疗降低了总胆固醇（P<0.001）和LDL胆固醇（P<0.001），但对高密度脂蛋白无影响。阿托伐他汀组的PAF-AH活性降低（平均变化-5.27±1.96nmol min(-1) ml(-1)，-6.51，-4.03；P<0.001），而安慰剂组未降低（平均变化1.02±1.64nmol min(-1) ml(-1)，0.15，2.20），且PAF-AH活性的变化与总胆固醇（P=0.03）和LDL胆固醇（P=0.03）的变化相关。
我们的结果表明阿托伐他汀对PAF-AH活性有降低作用，与其降脂作用相关，并且排除了PAF-AH在从磷脂中释放15-F(2t)-异前列腺素中的关键作用。
