A relationship between the activities of hepatic lanosterol 14 alpha-demethylase and 3-hydroxy-3-methylglutaryl-CoA reductase.
At 1-2 h after intragastric administration of ketoconazole, a cytochrome P-450 inhibitor, to rats, there was a 50-60% decrease in the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Inhibition reached a maximum at 6-12 h after the drug was given, but after 24 h enzyme activity was stimulated by 60%. The rates of synthesis of hepatic non-saponifiable lipids in vivo showed a similar time-dependent pattern of change. During the first few hours after drug administration, the hepatic cytochrome P-450-dependent metabolism of lanosterol was suppressed in vivo. However, 24 h after treatment, this activity was stimulated, an effect which was also observed by pre-treatment of the rats with the drug for several days. Suppression of hepatic HMG-CoA reductase and lanosterol 14 alpha-demethylase activities was accompanied by a relative increase in the accumulation of labelled polar sterols in the liver in vivo. In the intestine, ketoconazole also resulted in a rapid decline in the rate of synthesis of non-saponifiable lipids and an inhibition of lanosterol 14 alpha-demethylation in vivo. However, in contrast with the liver, there was no stimulation of non-saponifiable lipid synthesis after 24 h.
Marco de la Calle
C
C
Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, U.K.
Hwang
W
W
Pullinger
C R
CR
Gibbons
G F
GF
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System; D004790:Enzyme Induction / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007810:Lanosterol / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology*; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000378:metabolism
D008055:Lipids; D013261:Sterols; D007810:Lanosterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; D058886:Sterol 14-Demethylase; D007654:Ketoconazole