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]
- 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 NoInducerDetails Cerivastatin Cytochrome P450 2B6 Protein Humans UnknownInducerDetails - 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