Influence of 5-tridecylpyrazole-3-carboxylic acid, a new hypolipidaemic agent, on cholesteryl ester formation in rabbit intestinal mucosa.
The comparative effects of 5-tridecylpyrazole-3-carboxylic acid (TDPC), beta-sitosterol and melinamide on the esterification of cholesterol (CH) have been investigated in rabbit intestinal microsomes and cytosol in-vitro. The three agents did not show an effect on cholesteryl ester formation by cholesterol esterase (CEase). TDPC and beta-sitosterol did not affect cholesteryl oleate formation from oleoyl CoA by microsomal acyl CoA:cholesterol acyltransferase (ACAT), whereas melinamide significantly inhibited cholesteryl oleate formation. TDPC significantly inhibited the incorporation of oleic acid into cholesteryl oleate, which is associated with acyl CoA synthetase (ACS) plus ACAT in mucosal microsomes, at a concentration of 20-100 microM. On the other hand, 5-tridecylpyrazole-3-carbinol (TDPC-OH) a congener of TDPC, and beta-sitosterol did not show any effect. From these results, it is demonstrated that carboxylic moiety of TDPC is necessary to inhibit ACS in-vitro. According to the kinetic analytical results, it is suggested that TDPC acts as a competitive inhibitor of ACS. These results suggest that the inhibitory effect of TDPC on cholesteryl ester formation may be mediated by an inhibition of ACS activity. It is apparent from the data presented that there are substantial differences between TDPC, beta-sitosterol and melinamide with respect to their action on cholesteryl ester formation in rabbit intestinal mucosa.
Seki
K
K
Department of Development, Morishita Pharmaceutical Co. Ltd, Tokyo, Japan.
Horie
S
S
Watanabe
T
T
Suga
T
T
D000818:Animals; D002788:Cholesterol Esters / Q000096:biosynthesis*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D002787:Sterol Esterase / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism*
D002788:Cholesterol Esters; D000960:Hypolipidemic Agents; D011720:Pyrazoles; C044904:5-tridecylpyrazole-3-carboxylic acid; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase