Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor.

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Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M, Chiba K

Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor.

Drug Metab Dispos. 2005 Jul;33(7):924-9. Epub 2005 Mar 31.

PubMed ID

15802384 [ View in PubMed

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Abstract

Constitutive active (or androstane) receptor (CAR, NR1I3), a member of the nuclear receptor family, is a major regulator for induction of cytochrome P450 2B (CYP2B) genes by phenobarbital. Phenobarbital-like inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is a potent mouse CAR ligand that has been used to study CAR target genes in mice but does not activate human CAR (hCAR) or rat CAR (rCAR). Although 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) was reported to be an hCAR agonistic ligand, activation of hCAR by CITCO in cell-based reporter assay was weak. Therefore, we performed a screening of 50 drugs and chemicals using cell-based reporter assays to identify activators of hCAR. Among them, HMG-CoA reductase inhibitors (cerivastatin, simvastatin, fluvastatin, and atorvastatin) enhanced the hCAR-mediated transcriptional activation of phenobarbital-responsive enhancer module reporter gene by up to 3-fold. Similar activation by HMG-CoA reductase inhibitors was also observed with mouse and rat CARs. On the other hand, pravastatin did not activate hCAR at the concentrations tested (up to 30 microM). The extent of activation by the HMG-CoA reductase inhibitors was stronger than that by CITCO. Cerivastatin, simvastatin, fluvastatin, and atorvastatin induced CYP2B6 mRNA in stable hCAR-expressed FLC7 cells but not in original FLC7 cells. Therefore, we concluded that CAR mediates the effects of HMG-CoA reductase inhibitors on the induction of CYP2B genes, although HMG-CoA reductase inhibitors also activate pregnane X receptor. HMG-CoA reductase inhibitors such as cerivastatin would be useful to study for elucidating molecular and cellular mechanisms of hCAR.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Atorvastatin	Cytochrome P450 2B6	Protein	Humans	No	Inducer	Details
Cerivastatin	Cytochrome P450 2B6	Protein	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Atorvastatin	Approved	CYP2B6	1555	upregulated	Atorvastatin Calcium results in increased expression of CYP2B6 mRNA	19q13.2
Cerivastatin	Approved Withdrawn	CYP2B6	1555	upregulated	cerivastatin results in increased expression of CYP2B6 mRNA	19q13.2
Fluvastatin	Approved	CYP2B6	1555	upregulated	fluvastatin results in increased expression of CYP2B6 mRNA	19q13.2
Simvastatin	Approved	CYP2B6	1555	upregulated	Simvastatin results in increased expression of CYP2B6 mRNA	19q13.2