Effects of 6,6-difluorocholestanol and 7,7-difluorocholestanol on hepatic enzymes of cholesterol metabolism.
The effects of 6,6-difluorocholestanol and 7,7-difluorocholestanol on enzymes of hepatic liver cholesterol were examined. Neither compound affected the activity of 3-hydroxy-3-methylglutaryl-CoA reductase. 7,7-Diffluorocholestanol had no effect on the activity of acyl-CoA: cholesterol acyltransferase or cholesterol 7 alpha-hydroxylase. However, 6,6-difluorocholestanol was a competitive substrate for cholesterol in the esterification of cholesterol catalysed by the acyltransferase. 6,6-Difluorocholestanol also inhibited hydroxylation of cholesterol by cholesterol 7 alpha-hydroxylase but was not itself a substrate for this enzyme. These results show that substitutents in ring B of the sterol can have a significant effect on the binding of the sterol to enzymes and to the catalytic mechanism if the substituent is close to the groups in the molecule that participate.
Suckling
K E
KE
Department of Cellular Pharmacology, Smith Kline & French Research Ltd., Welwyn, U.K.
Jackson
B
B
Suffolk
R A
RA
Houghton
J D
JD
Suckling
C J
CJ
D000818:Animals; D001667:Binding, Competitive; D002777:Cholestanols / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D002777:Cholestanols; D004791:Enzyme Inhibitors; C059609:7,7-difluorocholestanol; C059608:6,6-difluorocholestanol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase