A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

doi:10.1006/bbrc.2002.6464

Biochemical and Biophysical Research Communications

Volume 291, Issue 2, 22 February 2002, Pages 378-384

https://doi.org/10.1006/bbrc.2002.6464 Get rights and content

Abstract

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.

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^☆: Abbreviations used: 25 OHC, 25-hydroxycholesterol; CAR, constitutive active receptor; CXR, chicken xenobiotic receptor; CYP, cytochrome P450; FXR/BAR, bile acid receptor; GAPDH, glyceraldehyde 3-phosphate-dehydrogenase; HMG, 3-hydroxy-3-methylglutaryl; LMH, leghorn male hepatoma; LXR, liver X receptor; PB, phenobarbital; PBRU, phenobarbital response unit; PXR, pregnane X receptor; RXR, retinoid X receptor; SQ1, squalestatin.

¹: Present address: INSERM U128, CNRS, 1919 Route de Mende, 34090 Montpellier cedex 5, France.

²: To whom correspondence and reprint requests should be addressed. Fax: +41 61 267 22 08. E-mail: [email protected].

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Regular ArticleA Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450☆

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Regular Article
A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450☆