Cholesterol derivative of a new triantennary cluster galactoside lowers serum cholesterol levels and enhances secretion of bile acids in the rat.
BACKGROUND
Previous studies have demonstrated that cholesterol-derivatized galactosides exert a hypocholesterolemic effect by inducing hepatic uptake of atherogenic lipoproteins by means of galactose-recognizing receptors in the liver. However, a prolonged infusion of high concentrations of these compounds was required for this effect, possibly because of low affinity for the galactose-recognizing asialoglycoprotein receptor on the parenchymal liver cell.


RESULTS
We have designed a new series of triantennary galactosides to optimize the affinity and specificity for this receptor. The affinity of a triantennary galactoside for the asialoglycoprotein receptor appeared to be dramatically enhanced by proper spacing of the three terminal galactose groups. In rats, a single injection of N-[tris-O-(3,6,9-trioxaundecanyl-beta-D-galacto- pyranosyl)methoxymethyl]methyl-N alpha-[1-(6-(5-cholesten-3 beta- yloxy)glycyl)adipyl]glycinamide [TG(20A)C], the cholesterol derivative of the most selective galactoside, causes a dose-dependent decrease of < or = 45% in the serum cholesterol concentration (P < .001). This decrease is mainly attributed to a decrease in the level of serum HDL (P = .0066) and, to a lesser extent, serum LDL (P = .036). In addition, TG(20A)C strongly enhances the bile-acid secretion in rats during the first 2 hours after administration, which indicates that TG(20A)C-induced clearance of cholesterol from the bloodstream is efficiently coupled to hepatic bile-acid secretion.


CONCLUSIONS
We conclude that TG(20A)C efficiently directs lipoproteins that contain cholesterol to the liver at a 30-fold-lower concentration than previously developed cholesterol-derived cluster galactosides. This newly developed approach to lower cholesterol levels may prove valuable for familial hypercholesterolemic patients or those with familial defective apolipoprotein B-100 who do not respond or who respond insufficiently, respectively, to conventional therapies.
Biessen
E A
EA
Leiden-Amsterdam Center for Drug Research, Sylvius Laboratory, University of Leiden, The Netherlands.
Vietsch
H
H
Van Berkel
T J
TJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000097:blood; D002788:Cholesterol Esters / Q000138:chemical synthesis / Q000494:pharmacology*; D005697:Galactosides / Q000138:chemical synthesis / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism
D000924:Anticholesteremic Agents; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D001647:Bile Acids and Salts; D002788:Cholesterol Esters; D005697:Galactosides; D008074:Lipoproteins; C092481:N-(tris-O-(3,6,9-trioxaundecanylgalactopyranosyl)methoxymethyl)methyl-N(alpha)-(1-(6-(5-cholesten-3-yloxy)glycyl)adipyl)glycinamide; D011956:Receptors, Cell Surface; D002784:Cholesterol