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.
Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address: qbpsern@hotmail.com.
Manuel
M
Serna
Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address: cwongb@ipn.mx.
Carlos
C
Wong-Baeza
Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address: jsantia@hotmail.com.
Juan-Carlos
JC
Santiago-Hernández
Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address: isabelbaeza@yahoo.com.
Isabel
I
Baeza
Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address: carloswongr@yahoo.com.
Carlos
C
Wong
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D020355:Cholates / Q000008:administration & dosage / Q000009:adverse effects*; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002934:Cinnamates / Q000737:chemistry / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
C552680:2,4,5-trimethoxycinnamic acid; D000924:Anticholesteremic Agents; D002756:Cholagogues and Choleretics; D020355:Cholates; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D002934:Cinnamates; C029010:cinnamic acid
2,4,5-Trimethoxycinnamic acid; Dimethoxycinnamic acids; HMG CoA reductase