title: Inhibitory effects of choleretic hydroxyacetophenones on ileal bile acid transport in rats.
abstract: The effects of the choleretic and cholesterol lowering compound, 2,4,6-trihydroxyacetophenone (THA) and its analog, 2,6-dihydroxyacetophenone (DHA), on ileal bile acid absorption were investigated in rats. THA inhibited taurocholate (TC) uptake into ileal brush-border membrane vesicles (BBMV), showing a maximum inhibition of 50%, whereas DHA completely inhibited TC uptake into ileal BBMV. THA exhibited competitive inhibition with a Ki of 9.88 mM, while DHA showed non-competitive inhibition with a Ki of 7.65 mM. Both total and ouabain-sensitive basolateral membrane (BLM) Na+-K+-ATPase activities, which are essential for maintenance of the Na+-gradient for bile acid transport, were inhibited by THA and DHA in a dose-dependent manner. The inhibition of BLM ATPase was uncompetitive with a Ki of 10.1 and 5.0 mM for THA and DHA, respectively. Administration of THA or DHA (400 micromol/kg) twice a day, to hypercholesterolemic rats for 3 weeks caused similar and marked reductions in plasma cholesterol to 60% of the cholesterol-fed controls. The data suggest that the inhibitory actions of THA and DHA on two essential components of ileal bile acid recycling to liver could, in part, contribute to the cholesterol lowering effect of the hydroxyacetophenone compounds. These effects on decreasing bile acid recycling, in combination with their potent choleretic effect, accelerating biliary excretion of bile acids, are responsible for the effective cholesterol lowering capacities of these compounds.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Bangkok 10400, Thailand.
authors.forename: Jainuch
authors.initials: J
authors.lastname: Kanchanapoo
authors.forename: Mrinalini C
authors.initials: MC
authors.lastname: Rao
authors.forename: Samaisukh
authors.initials: S
authors.lastname: Sophasan
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D013656:Taurocholic Acid; C019339:2,6-dihydroxyacetophenone; C107067:2,4,6-trihydroxyacetophenone; D002784:Cholesterol; D000254:Sodium-Potassium-Exchanging ATPase