Effects of pregnenolone-16 alpha-carbonitrile on the metabolism of cholesterol in rat liver microsomes.
The effects of pregnenolone-16 alpha-carbonitrile (PCN) on hepatic metabolism of cholesterol were studied in rat liver microsomes in order to clarify the underlying mechanisms of the PCN-induced biliary hypersecretion of cholesterol. Male Sprague-Dawley rats were fed a diet supplemented with 0.05% of PCN for one week. The microsomal activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, regulating cholesterol biosynthesis, decreased from 577 +/- 46 (SEM) to 367 +/- 38 pmol/min/mg protein compared to the controls. Cholesterol 7 alpha-hydroxylase activity, governing bile acid synthesis, was 9.0 +/- 1.1 pmol/min/mg protein in the treated group and 34.8 +/- 7.4 pmol/min/mg protein in the controls, a reduction of 74% (P < 0.01). The acyl CoA:cholesterol acyltransferase (ACAT) activity, catalyzing the esterification of cholesterol, remained unchanged, as did the levels of total and free cholesterol in liver homogenates and microsomes. The results of this study provide evidence that the increase in biliary cholesterol secretion during PCN treatment is not caused by a change in ACAT activity, but can be explained by a decreased catabolism of cholesterol to bile acids.
Ståhlberg
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Department of Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011285:Pregnenolone Carbonitrile; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase