Possible hypocholesterolemic action of 15-ketosterol: replacement of dietary cholesterol absorption

15-Ketosterol (5 alpha-cholest-8(14)-en-3 beta-ol-15-one), a potent inhibitor for sterol synthesis, has shown hypocholesterolemic effects in rodents, baboons, and rhesus monkeys. In recent studies we demonstrated that 15-ketosterol also exerted regulation on the input of cholesterol at the level of intestinal absorption. When Sprague Dawley rats were fed 0.05% 15-ketosterol in their chow for 10 days, a decrease in the absorption of cholesterol into lymph by 62 +/- 8% (n = 4) was observed in the first 48 hrs after the intragastic infusion of radiolabelled cholesterol. The absorption of cholesterol replaced by 15-ketosterol was further evidenced in the demonstration that the rats had a much more efficient rates of absorbing 15-ketosterol. Infusing rats with equal amount of the two sterols, the amount of 15-ketosterol absorbed was 3-4 fold that of cholesterol in the initial 10 hrs. 15-Ketosterol was absorbed in and mainly esterified with 18:1 packed into intestinal chylomicrons. Upon the intravenous injection of chylomicrons isolated from other animals receiving 3H-15-ketosterol intragastrically, the rapid appearance of radioactivity in the liver suggested that chylomicrons were taken up effectively. Ketosteryl ester was hydrolyzed back to 15-ketosterol in the liver. The metabolic fate of 15-ketosterol was very different from that of cholesterol. Over 85% of the administered dose was recovered in the bile 38 hrs after intravenous injection of 15-ketosterol. In contrast, only 15% of cholesterol and/or its metabolites was slowly secreted in the bile.(ABSTRACT TRUNCATED AT 250 WORDS)