Inhibitors of sterol synthesis. Metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one after intravenous administration to bile duct-cannulated rats.
The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one has been studied after intravenous administration to bile duct-cannulated rats. Very rapid and substantial conversion of the 15-ketosterol to polar biliary metabolites was observed in both male and female rats. For example, upon intravenous injection of [4-14C]5 alpha-cholest-8(14)-en-3 beta-ol-15-one to male bile duct-cannulated rats, approximately 86% of the administered 14C was recovered in bile in the first 38 h. Of the total amount of 14C recovered in bile in 38 h, approximately 50% was excreted in bile in the first 70 min and approximately 90% was excreted within 8 h after the injection of the 15-ketosterol. A substantial fraction of the polar biliary metabolites was shown to undergo enterohepatic circulation. Of the radioactivity derived from the labeled 15-ketosterol which was not recovered in bile or other excreta at 48 h after the intravenous administration of the 15-ketosterol, most (approximately 79%) was recovered in the form of cholesterol and cholesteryl esters of blood and the various tissues. The very substantial and rapid biliary excretion of polar metabolites of the 15-ketosterol (or of cholesterol derived from the 15-ketosterol), coupled with inhibition of the intestinal absorption of cholesterol by the 15-ketosterol, may contribute to the overall hypocholesterolemic action of the 15-ketosterol which has been observed in rodents and in nonhuman primates by providing a metabolic pathway(s) wherein a substantial fraction of the absorbed 15-ketosterol is rapidly removed from the body by biliary excretion in the form of polar metabolites.
Schroepfer
G J
GJ
Department of Biochemistry, Rice University, Houston, Texas 77251.
Chu
A J
AJ
Needleman
D H
DH
Izumi
A
A
Nguyen
P T
PT
Wang
K S
KS
Little
J M
JM
Sherrill
B C
BC
Kisic
A
A
D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts; D002404:Catheterization; D002782:Cholestenes / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D004386:Duodenum; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D013152:Splanchnic Circulation
D002782:Cholestenes; D002783:Cholestenones; C015073:cholest-8(14)-en-3-ol-15-one; D002784:Cholesterol