Inhibitors of sterol synthesis. A major role of chylomicrons in the metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one in the rat.
The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one (I), a potent regulator of cholesterol (Chol) metabolism which has significant hypocholesterolemic activity upon oral administration to animals, has been investigated in male rats. After intragastric administration of [2,4-3H] I and [4-14C]Chol in triolein to intestinal lymph duct-cannulated rats, most of the 3H of the lymph was associated with chylomicrons. Most of the 3H in the chylomicrons was associated with fatty acid esters of I and the oleate ester represented the major species of the esters of I. After intravenous injection of the isolated doubly-labeled chylomicrons to intact rats, rapid clearance of 3H and 14C from blood was observed which was associated with a rapid and selective uptake of 3H and 14C by liver. The rate of disappearance of 3H from blood and the rate of uptake of 3H by liver were similar, if not identical, to those for 14C. In contrast, the disappearance of 3H from the liver was much more rapid than that of 14C. Studies of the distribution of 3H in liver demonstrated rapid formation of free I and the formation of [3H]Chol. In addition, significant amounts of the 3H in liver were associated with polar materials, a finding which was not observed in the case of 14C. After intravenous administration of the doubly-labeled chylomicrons to bile duct-cannulated rats, very rapid and substantial metabolism of the administered 3H to polar biliary metabolites was observed. The bulk of the 3H not recovered in bile at 49 h after the injection of the labeled chylomicrons was recovered in blood and tissues and almost all (integral of 94%) of this material was associated with Chol and Chol esters. The combined results indicate an important role for chylomicrons in the overall metabolism of I. The selective delivery of I to liver as its oleate ester in chylomicrons (or, more probably, as chylomicron remnants) and the subsequent metabolism of the oleate ester of I in liver has important consequences with respect to the actions of I which are discussed herein.
Schroepfer
G J
GJ
Department of Biochemistry, Rice University, Houston, Texas.
Christophe
A
A
Chu
A J
AJ
Izumi
A
A
Kisic
A
A
Sherrill
B C
BC
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D002782:Cholestenes / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002914:Chylomicrons / Q000302:isolation & purification / Q000502:physiology*; D007422:Intestines / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008196:Lymph / Q000032:analysis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000096:biosynthesis*
D000924:Anticholesteremic Agents; D002782:Cholestenes; D002783:Cholestenones; D002914:Chylomicrons; D013261:Sterols; C015073:cholest-8(14)-en-3-ol-15-one; D002784:Cholesterol