A Link between cholesterol levels and phenobarbital induction of cytochromes P450.
Squalestatin1 (SQ1), a potent inhibitor of squalene synthase produced a dose-dependent induction of cytochromes P450 CYP2H1 and CYP3A37 mRNAs in chicken hepatoma cells. The effect of SQ1 was completely reversed by 25-hydroxycholesterol. Bile acids elicited an induction of CYP3A37 and CYP2H1 mRNA. Bile acids also reduced the phenobarbital induction of CYP2H1 but not of CYP3A37 mRNA. The effects of SQ1 and its reversal by 25-hydroxycholesterol and the effects of bile acids were reproduced in reporter gene assays with a phenobarbital-responsive enhancer unit of CYP2H1. These data suggest that an endogenous molecule related to cholesterol homeostasis regulates induction of drug-inducible CYPs.
Ourlin
Jean-Claude
JC
Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, Basel, Switzerland.
Handschin
Christoph
C
Kaufmann
Michel
M
Meyer
Urs A
UA
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002645:Chickens; D002784:Cholesterol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D017930:Genes, Reporter; D006888:Hydroxycholesterols / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D014233:Tricarboxylic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001647:Bile Acids and Salts; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D014233:Tricarboxylic Acids; C075117:squalestatin 1; C007997:25-hydroxycholesterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D010634:Phenobarbital