Hypocholesterolemic and choleretic effects of three dimethoxycinnamic acids in relation to 2,4,5-trimethoxycinnamic acid in rats fed with a high-cholesterol/cholate diet

Background 2,4,5-trimethoxycinnamic acid (2,4,5-tmc) is the major and non-toxic metabolite of α-asarone,which retains hypocholesterolemic and choleretic activities. we compared the activities of 2,4,5-tmc with those of 2,4-dimethoxycinnamic acid (2,4-dmc),3,4-dmc and 3,5-dmc,to understand the role of the methoxyls on carbons 2,4 and 5 on the pharmacologic properties of these compounds. methods the methoxycinnamic acids were administered to high-cholesterol/cholate-fed rats. we measured bile flow,and quantified bile acids,phospholipids and cholesterol in bile,and cholesterol and cholesterol-lipoproteins in serum. the inhibition of hmg-coa reductase by the methoxycinnamic acids was evaluated in vitro. results the four methoxycinnamic acids decreased serum cholesterol,without affecting the concentration of hdl-cholesterol. 2,4,5-tmc produced the highest decrease in ldl-cholesterol,73.5%,which exceeds the range of statins (20-40%),and produced the highest inhibition of the activity of hmg-coa reductase. 3,4-dmc produced the highest increase in bile flow,bile acids and phospholipids concentrations,and reduction in bile cholesterol,which led to a decrease in the biliary cholesterol saturation index. conclusions 2,4,5-tmc (which has three methoxyls) had the highest hypocholesterolemic activity,while 3,4-dmc,which lacks the methoxyl in carbon 2 but conserves the two other methoxyls in an adjacent position,had the highest choleretic activity and a probable cholelitholytic activity. in methoxycinnamic acids with two methoxyls in non-adjacent positions (2,4-dmc and 3,5-dmc),the hypocholesterolemic and choleretic activities were not as evident. 2,4,5-tmc and 3,4-dmc,which did not cause liver damage during the treatment period,should be further explored as a hypocholesterolemic and choleretic compounds in humans. © 2014 institute of pharmacology,polish academy of sciences.