In vitro inhibitory effects of plumbagin,the promising antimalarial candidate,on human cytochrome P450 enzymes

Objective:To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450(CYP),ie.,CYP1A2,CYP2C19,and CYP3A4 using human liver microsomes in ritro.Methods:Inhibitory effects of plumbagin on the three human CYP isoformswere investigated using pooled human liver microsomes.Phenacetin O-deethylation,omeprazole hydroxylation and nifedipine oxidation were used as selective substrates for CYP1A2,CYP2C19 and CYP3A4 activities,respectively.Concentrations of paracetamol,5-hydroxyomeprazole,and oxidized nifedipine were determined in microsomal incubation mixture using high performance liquid chromatography.Results:Plumbagin showed significantinhibitory effects on all CYP isoforms.but with the most potent activity on CYP2C19-mediated omeprazole hydroxylation.The IC50(concentration that inhibits enzyme activity by 50%) values of plumbagin and nootkatone(selective inhibitor) for CYP2C19 were(0.78±0.01) and(27.31±0.66) μM,respectively.The inhibitory activities on CYP1 A2-mediated phenacetin O-deethylation and CYP3A4-mediated nifedipine oxidation were moderate.The IC_(50) values of plumbagin and-naphthoflavone(selective inhibitor) for CYP1A2 were(1.39±0.01) and(0.02±.0.36) μM,respectively.The corresponding IC_(50) values of plumbagin and ketoconazole(selective inhibitor) for CYP3A4 were(2.37+0.10) and(0.18±0.06) μM,respectively.Conclusions:Clinical relevance of the interference of human drug metabolizing enzymes should be aware of for further development scheme of plumbagin as antimalarial drug when used in combination with other antimalarial drugs which are metabolized by these CYP isoforms.

叠氮钠造成脑线粒体损伤模型的研究现状

现已证明 ,线粒体缺陷与阿尔茨海默病 (AD)的发生密切相关 ,其中AD患者细胞色素C氧化酶 (COX)活性的降低明显且特异。叠氮钠 (NaN3 ) ,一种特异性COX抑制剂 ,可以损伤线粒体活性 ,建立具有部分类似AD病理改变的动物和细胞模型。它可以导致动物学习记忆功能障碍 ,其可能的机制包括细胞骨架结构破坏 ,Aβ沉积 ,氧化损伤 ,离子内稳态破坏 ,细胞膜损伤以及神经递质异常。NaN3 造成的脑线粒体损伤模型为AD机理和治疗药物的研究提供了新的途径。

增力祛疲口服液对游泳致疲劳大鼠骨骼肌和血液生化指标的影响

目的 :探讨增力祛疲口服液抗运动性疲劳作用的现代机制。方法 :选用游泳训练导致大鼠运动性疲劳模型 ,用生化测定和细胞化学分析的方法 ,研究大鼠骨骼肌中糖原、SDH、LDH、LPO、Ca+ + 、K+ 的含量变化以及血清睾酮 (T)、皮质醇 (C)、T/C值、SOD活性、MDA含量的变化 ,观察增力祛疲口服液对其变化的影响。结果 :与正常组比较 ,对照组大鼠骨骼肌组织糖原含量、Ca+ + 、K+ 含量和血清T含量、SOD含量及T/C比值显著降低 ,而骨骼肌组织中LDH活性增强、LPO含量增加 ,血清中MDA和C含量显著增加 ,(P <0 .0 5 ) ;与对照组比较 ,实验组大鼠上述指标均显著改善。结论 :该药有利于骨骼肌组织疲劳后的功能恢复 ,有增强抗疲劳的良好作用 ,其机理与改善骨骼肌的新陈代谢和提高清除自由基的能力有关。

枸杞多糖对运动性骨骼肌疲劳恢复的细胞定量化学分析和电镜观察

通过小鼠实验，用枸杞多糖解除运动性骨骼肌疲劳，以显微分光光度计进行琥珀酸脱氢酶（ＳＤＨ）和糖原的定性定量分析，并于透射电镜下观察超微结构的变化。结果显示，运动疲劳（Ｂ）组糖原含量明显降低，各类肌纤维与对照（Ａ）组比较Ｐ＜０．００１；ＳＤＨ活性增加，各类肌纤维与Ａ组比较Ｐ＜０．００１。服用枸杞多糖（Ｃ）组糖原含量增加，各类肌纤维与Ａ组比较Ｐ＜０．００１；与Ｂ组比较Ｐ＜０．００１；ＳＤＨ反应较Ｂ组更深，各类肌纤维与Ａ组比较Ｐ＜０．００１，若与Ｂ组比较，则其中Ｉ（慢肌）型和Ⅱ（中间肌）型Ｐ＜０．００１，而Ⅱ（快肌）型则Ｐ＞０．０５。超微结构显示，Ｂ组线粒体增多且体积明显增大，呈肿胀状态；Ｃ组全无此类改变，提示服用枸杞多糖后可解除疲劳，其中以Ｉ（慢肌）型肌纤维效果尤佳。