Arylsulfonate esters as hypocholesteremic agents: III. Mechanism of action studies

Abstract

The mechanism responsible for the hypocholestermic action of arylsulfonate esters of long chain fatty alcohols has been studied with rats fed either normocholesteremic or hypercholesteremic (1% cholesterol plus 0.5% glycoholate) diets. Linoleyl tosylate is more effective in lowering plasma and liver cholesterol levels of rats on the hypercholesteremic diet than several other hypocholesteremic agents tested. Linoleyl tosylate does not redistribute cholesterol to extrahepatic tissues nor inhibit hepatic cholesterol biosynthesis. Linoleyl tosylate is not effective in counteracting Triton-induced hypercholesteremia nor in lowering plasma cholesterol levels of the suckling rat. Linoleyl tosylate increases the fecal elimination of dietary [4(-14)C] cholesterol and prevents its accumulation in blood and liver. Oleyl p-(n-decyl) benzene sulfonate also prevents the apparent absorption of [26(-14)C] cholesterol from the gastrointestinal tract. Linoleyl tosylate increases the fecal excretion of neutral sterols but not of bile acids. The results indicate that the arylsulfonate esters of long chain fatty alcohols lower body cholesterol levels by inhibiting cholesterol absorption from the gastrointestinal tract. Exactly how absorption is inhibited is not clear, but linoleyl tosylate was found to stimulate the activity of cholesteryl esterase prepared from the intestinal mucosa.

The effect of arylsulfonate esters on cholesterol‐aggravated atherosclerosis in white carneau pigeons

“…These studies demonstrate that arylsulfonate esters of fatty alcohols when incorporated into the diet at a level of 0.25% effectively reduce the accumulation of both plasma and liver cholesterol in White Carneau pigeons receiving a hypercholesterolemic regimen of 0.25% cholesterol and 10% lard coated on Purina pigeon pellets. These results are comparable to those observed in rats subjected to diets containing 1% cholesterol and 0~ sodium glycocholate and dietary levels of arylsulfonate esters of fatty alcohols of 0o15% (2). These compounds were found to be ineffective in lowering plasma and liver cholesterol concentrations in normocholesterolemic pigeons, an observation consistent with their lack of effect in normocholesterolemic rats (2) and consistent with inhibition of cholesterol absorption as a mode of action.…”

“…Decyl p-toluenesulfonate was ineffective in lowering plasma cholesterol levels in birds receiving no exogenous cholesterol in the diet. This response is consistent with the cholesterol absorption inhibition properties of the arylsulfonates (2) and is in agreement with results using normocholesterolemic rats. Hepatic cholesterol levels were slightly but significantly elevated in these birds.…”

“…It has been shown by Quackenbush et al (l) and MacNintch et al (2) that arylsulfonate esters of various log chain fatty alcohols are potent cholesterol-lowering agents when administered orally or parenterally to the cholesterol-glycocholate-fed rat. Results indicate that these compounds lower body cholesterol levels by inhibiting cholesterol absorption from the gastrointestinal tract.…”

Arylsulfonate esters of fatty alcohols: IV. Effects on cholesterol catabolism

“…The mechanism of cholesterol-lowering by these compounds has not been completely established. Linoleyl p-toluenesulfonate (LTS) does not inhibit cholesterol synthesis in liver in vivo or in vitro nor does it cause a redistribution of cholesterol to other tissues (3 (3) in a manner similar to the structurally related hypocholesterolemic agent, (-)N-[o~phenyl-/3-(p-tolyl)ethyl]linoleamide (4). Although initial studies with normocholesterolemic rats showed no increase in fecal excretion of acidic steroids (3), this report presents evidence that arylsulfonates can effect bile acid metabolism and cholesteryl ester hydrolase activity.…”