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)
Chu
A J
AJ
Biochemistry Department, Rice University, Houston, TX 77251.
D000818:Animals; D000924:Anticholesteremic Agents; D001646:Bile / Q000378:metabolism; D002782:Cholestenes / Q000494:pharmacology*; D002783:Cholestenones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002791:Cholesterol, Dietary / Q000378:metabolism / Q000493:pharmacokinetics*; D002914:Chylomicrons / Q000493:pharmacokinetics; D004951:Esterification; D007408:Intestinal Absorption / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008196:Lymph / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000924:Anticholesteremic Agents; D002782:Cholestenes; D002783:Cholestenones; D002791:Cholesterol, Dietary; D002914:Chylomicrons; C015073:cholest-8(14)-en-3-ol-15-one