Hepatic microsomal activities of cholesterol 7α-hydroxylase and 3-hydroxy-3-methylglutaryl-coa reductase in the prairie dog: An animal model for cholesterol gallstone disease

Abstract The prairie dog is a useful experimental animal model for studies of cholesterol gallstone pathogenesis. The unique susceptibility to rapid induction of gallstones solely by feeding of a 1.2% cholesterol diet in this species could result from low levels of hepatic cholesterol 7α-hydroxylase. With optimal assay conditions in hepatic microsomes, a basal specific activity of about 25 pmol/min per g protein was found. Administration of diets containing 1.2% cholesterol or 5% cholestyramine caused hydroxylase levels to increase 60 and 250%, respectively. This response pattern is similar to that observed in other species under the same conditions, indicating that abnormally low basal or inappropriately unresponsive hydroxylase levels are not susceptibility factors unique to this model. With optimal assay conditions for hydroxymethylglutaryl-CoA reductase, a K m of 32.5 μM ( S -HMG-CoA) and basal specific activities of between 60 and 175 pmol/min per mg protein were found. Following feeding of either sodium chenodeoxycholate or sodium cholate, in reasonable pharmacologic doses, no suppression of hydroxylase and reductase levels was found. These findings undermine the widely held view that the therapeutic effect of oral chenodeoxycholate in man for cholesterol gallstone dissolution is directly mediated by suppression of the activities of these enzymes.