Regulation of bile acid synthesis in humans: studies on cholesterol 7 alpha-hydroxylation in vivo.
Over the last few years important progress has been made on the quantitation of cholesterol 7 alpha-hydroxylation, the rate-limiting step of bile acid synthesis. The use of a technique based on the determination of body water tritium enrichment after i.v. administration of [7 alpha-3H] cholesterol has allowed in vivo investigation of this step in humans in different experimental conditions. The cholesterol 7 alpha-hydroxylation rate was not affected by the administration of the hydrophilic bile acid ursodeoxycholic acid (UDCA) whereas it was significantly reduced by the more hydrophobic chenodeoxycholic acid (CDCA) and even more so by the strongly hydrophobic deoxycholic acid (DCA). The administration of cholestyramine induced a significant dose-related increase of 7 alpha-hydroxylation along with a correspondent decrease in plasma cholesterol. The administration of simvastatin exerted no effect on cholesterol 7 alpha-hydroxylation despite a marked decrease in serum cholesterol. Treatment with fibrates reduced plasma lipid levels and 7 alpha-hydroxylation rates. Hydroxylation rates were unchanged in familial hypercholesterolaemia and increased in familial combined hyperlipidaemia. These data suggest that in humans bile acid synthesis can be affected by quantitative and qualitative alterations of the enterohepatic circulation of bile acids. Changes in cholesterol 7 alpha-hydroxylation rates may be associated with alterations in plasma lipid levels, but such a relationship is ill-defined and seems to vary with the different experimental models.
Bertolotti
M
M
Istituto di Patologia Medica, Università di Modena, Italy.
Abate
N
N
Loria
P
P
Concari
M
M
Guicciardi
M E
ME
Dilengite
M A
MA
Bozzoli
M
M
Carubbi
F
F
Carulli
N
N
D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000096:biosynthesis* / Q000502:physiology*; D002635:Chenodeoxycholic Acid / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000502:physiology; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D006949:Hyperlipidemias / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000502:physiology
D001647:Bile Acids and Salts; D000960:Hypolipidemic Agents; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase