The role of cytochrome P450 in the regulation of cholesterol biosynthesis.
A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51, encodes lanosterol 14alpha-demethylase, the first step in the conversion of lanosterol into cholesterol in mammals. The biosynthetic intermediates of lanosterol 14alpha-demethylation are oxysterols, which inhibit HMG-CoA reductase and sterol synthesis in mammalian cells in vitro. These oxysterols (5alpha-lanost-8-en-3beta,32-diol and 3beta-hydroxy-5alpha-lanost-8-en-32-al) are efficiently converted into cholesterol in vitro and are generally considered to be natural cholesterol precursors. When added to hepatocytes in high concentrations, besides their conversion into cholesterol, they are also rapidly metabolized into more polar sterols and into steryl esters. The 15alpha- and 15beta-hydroxy epimers of 5alpha-lanost-8-en-3beta-ol are also rapidly metabolized into more polar sterols and steryl esters but are not converted efficiently into cholesterol. Polar sterol formation from all these oxysterols is dependent on an active form of cytochrome P450. Oxysterols are potent regulators of the activities of transcription factors of the sterol regulatory element-binding protein family and of liver X-receptor alpha. It is proposed that the rapid, cytochrome P450-dependent metabolism of naturally occurring regulatory oxysterols provides a route for their deactivation so that they become incapable of affecting gene transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents the inactivation of such oxysterols, leading to a prolonged suppression of hepatic HMG-CoA reductase in vivo and in vitro.
Gibbons
Geoffrey F
GF
Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX2 6HE, United Kingdom. geoff.gibbons@metabolic-research.oxford.ac.uk
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases