Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster.
BACKGROUND
Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol.


RESULTS
The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed 3H-labeled cholesteryl oleate along with inhibitor 1, 0-200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED50 of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups.


CONCLUSIONS
Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption.
Heidrich
John E
JE
Albuquerque Avian, Exotic, and Small Animal Clinic, 8414 Fourth Street, NW, Albuquerque, NM 87114, USA. jheidric@swcp.com
Contos
Linda M
LM
Hunsaker
Lucy A
LA
Deck
Lorraine M
LM
Vander Jagt
David L
DL
D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000378:metabolism*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006868:Hydrolysis; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D011753:Pyrones / Q000494:pharmacology* / Q000633:toxicity; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism
C487772:6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D011753:Pyrones; C054784:bile salt-stimulated lipase; D002787:Sterol Esterase