Mechanism of the inhibition of cholesterol absorption by DL-melinamide: inhibition of cholesterol esterification.
In order to elucidate the mechanism of action of DL-melinamide [DL-MA, N-(alpha-methylbenzyl)linoleamide], an inhibitor of cholesterol absorption, the effect of DL-MA on esterification of cholesterol in the mucosa of rabbit small intestine was studied. DL-MA inhibited acyl CoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) activity in the mucosal microsomes, with 50% inhibition occurring at approximately 0.5 microM. On the other hand, DL-MA had no effect on the cholesterol esterase (EC 3.1.1.13) activity in the mucosal cytosol. Kinetic studies indicate that DL-MA is an uncompetitive inhibitor of ACAT. D-MA, one of the two optical isomers of DL-MA, was found to be a more effective inhibitor of ACAT than L-MA, another isomer. This finding indicates that the inhibition of cholesterol absorption by DL-MA depends on the inhibition of ACAT by this compound, in view of the fact that D-MA is a more effective inhibitor of cholesterol absorption than L-MA.
D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D008041:Linoleic Acids / Q000494:pharmacology*; D008297:Male; D053284:Polyunsaturated Alkamides; D011817:Rabbits; D013237:Stereoisomerism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D014280:Triglycerides / Q000096:biosynthesis
D000178:Acrylamides; D008041:Linoleic Acids; D053284:Polyunsaturated Alkamides; D014280:Triglycerides; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C001757:N-(2-methylbenzyl)linoleamide