title: Effect of natural and structurally modified bile acids on cholesterol metabolizing enzymes in rat liver microsomes. II.
abstract: The effect of ursodeoxycholic acid analogues bearing modifications at the side-chain moiety of the molecule was tested on cholesterol 7 alpha-hydroxylase and HMG-CoA reductase in rat liver microsomes. The compounds included 23 R,S mixture and the single isomers 23R and 23S of 23 methylursodeoxycholic acid (23-methyl UDCA), the isomeric mixture (cis + trans) of 3 alpha,7 beta-dihydroxy-20,22-methylen-5 beta-cholan-23-oic acid (norcypro-UDCA) and the corresponding single isomers. Each steroid was added to liver microsomes as the sodium salt, at concentrations ranging from 25 to 200 microM. Isomers 23R and 23S of 23-methyl-UDCA inhibited cholesterol 7 alpha-hydroxylase in a concentration-dependent manner. The inhibitory capacity was similar for the two isomers. The extent of inhibition of the analogues was greater than that of the parent compound UDCA. Shortening of the side-chain in norcypro-UDCA resulted in a partial loss of the inhibitory effect, as compared to cypro-UDCA (3 alpha,7 beta-dihydroxy-22,23-methylen-5 beta-cholan-24-oic acid). None of these bile acid derivatives affected the activity of the enzyme HMG-CoA reductase.
authors.affiliation: Institute of Pharmacological Sciences, Faculty of Pharmacy, University of Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: De Fabiani
authors.forename: M
authors.initials: M
authors.lastname: Crestani
authors.forename: L
authors.initials: L
authors.lastname: Fasoli
authors.forename: E
authors.initials: E
authors.lastname: Bosisio
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; C069594:23-methylursodeoxycholic acid; D014580:Ursodeoxycholic Acid; C069597:3,7-dihydroxy-20,22-methylenecholan-23-oic acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase