Gebhardt R
Physiologisch-chemisches Institut der Universität, D-72076 Tübingen, Germany.
J Pharmacol Exp Ther. 1998 Sep;286(3):1122-8.
High-dose aqueous extracts from artichoke leaves were found to inhibit cholesterol biosynthesis from 14C-acetate in primary cultured rat hepatocytes in a concentration-dependent biphasic manner with moderate inhibition (approximately 20%) between 0.007 and 0.1 mg/ml and more strong inhibition at 1 mg/ml. Cytotoxic effects detected by lactate dehydrogenase leakage and the 3-[4, 5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide-assay were restricted to higher concentrations. Replacement of 14C-acetate by 14C-mevalonate largely omitted the inhibiting effect of artichoke extracts indicating an inhibition at the level of hydroxymethylglutaryl-CoA-reductase. However, no direct inhibition of this enzyme could be detected and no other enzymic steps later in the biosynthetic pathway for cholesterol seemed to be affected. Instead, inhibition was found to occur in a time-dependent manner, to last for several hours even after washing out the extracts by fresh medium and to be fully reversible within 20 hr after removal of the extracts. In addition, the stimulation of HMGCoA-reductase activity by insulin was efficiently blocked by the extracts, although other insulin-dependent phenomena, such as increased lactate production, were not influenced. These results suggest an indirect modulation of hydroxymethylglutaryl-CoA-reductase activity as the most likely inhibitory mechanism of the artichoke extracts. Screening of several known constituents of artichoke extracts revealed that cynaroside and particularly its aglycone luteolin were mainly responsible for inhibition, whereas chlorogenic acid was much less effective and caffeic acid, cynarin and other dicaffeoylquinic acids were without significant influence. Indeed, luteolin also efficiently blocked the insulin effect on cholesterol biosynthesis. In conclusion, these results demonstrate that artichoke extracts may inhibit hepatic cholesterol biosynthesis in an indirect but efficient manner and, thus, may contribute via this action to the recently confirmed hypolipidemic influence of this phytopharmacon in man.
研究发现，洋蓟叶的高剂量水提取物能够以浓度依赖性双相方式抑制原代培养大鼠肝细胞中由14C-乙酸盐合成胆固醇的过程，在0.007至0.1毫克/毫升之间有中度抑制作用（约20%），在1毫克/毫升时抑制作用更强。通过乳酸脱氢酶泄漏和3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑检测到的细胞毒性作用仅限于较高浓度。用14C-甲羟戊酸替代14C-乙酸盐在很大程度上消除了洋蓟提取物的抑制作用，表明其抑制作用发生在羟甲基戊二酰辅酶A还原酶水平。然而，未检测到对该酶的直接抑制作用，胆固醇生物合成途径中该酶之后的其他酶促步骤似乎也未受影响。相反，发现抑制作用呈时间依赖性，即使在用新鲜培养基洗去提取物后仍持续数小时，并且在去除提取物后20小时内可完全逆转。此外，提取物有效阻断了胰岛素对HMGCoA还原酶活性的刺激作用，尽管其他胰岛素依赖性现象，如乳酸生成增加，未受影响。这些结果表明，洋蓟提取物最可能的抑制机制是间接调节羟甲基戊二酰辅酶A还原酶活性。对洋蓟提取物的几种已知成分进行筛选发现，洋蓟苷及其苷元木犀草素是主要的抑制成分，而绿原酸的效果要差得多，咖啡酸、洋蓟酸和其他二咖啡酰奎宁酸则无显著影响。事实上，木犀草素也有效阻断了胰岛素对胆固醇生物合成的作用。总之，这些结果表明，洋蓟提取物可能以间接但有效的方式抑制肝脏胆固醇生物合成，因此，可能通过这一作用对最近证实的这种植物药对人体的降血脂作用做出贡献。
