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Title: Species-dependent and receptor-selective action of bilobalide on the function of constitutive androstane receptor and pregnane X receptor
Authors: Lau, A.J 
Yang, G
Rajaraman, G
Baucom, C.C
Chang, T.K.H
Keywords: 16alpha cyanopregnenolone
constitutive androstane receptor
cytochrome P450 2B
cytochrome P450 2B1
cytochrome P450 2B6
cytochrome P450 3A
cytochrome P450 3A23
cytochrome P450 3A4
messenger RNA
pregnane X receptor
unclassified drug
animal cell
concentration response
controlled study
drug mechanism
enzyme activation
enzyme activity
gene expression
gene location
gene targeting
human cell
liver cell
nucleotide sequence
priority journal
protein function
protein localization
protein targeting
reporter gene
Cell Line, Tumor
Cells, Cultured
Hep G2 Cells
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid
Species Specificity
Issue Date: 2012
Publisher: American Society for Pharmacology and Experimental Therapeutics
Citation: Lau, A.J, Yang, G, Rajaraman, G, Baucom, C.C, Chang, T.K.H (2012). Species-dependent and receptor-selective action of bilobalide on the function of constitutive androstane receptor and pregnane X receptor. Drug Metabolism and Disposition 40 (1) : 178-186. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Bilobalide is a naturally occurring sesquiterpene trilactone with therapeutic potential in the management of ischemia and neurodegenerative diseases such as Alzheimer's disease. In the present study, we investigated the effect of bilobalide on the activity of rat constitutive androstane receptor (rCAR) and rat pregnane X receptor (rPXR) and compared that with human CAR (hCAR) and human PXR (hPXR). Bilobalide activated rCAR in a luciferase reporter gene assay and increased rCAR target gene expression in cultured rat hepatocytes, as determined by the CYP2B1 mRNA and CYP2B enzyme activity (benzyloxyresorufin O-dealkylation) assays. This increase in hepatocyte CYP2B1 expression by bilobalide was not accompanied by a corresponding increase in rCAR mRNA level. In contrast to the activation of rCAR, the activity of rPXR, hCAR, and hPXR was not influenced by this chemical in cell-based reporter gene assays. Consistent with these results, bilobalide did not alter rPXR, hCAR, or hPXR target gene expression in rat or human hepatocytes, as evaluated by the CYP3A23, CYP2B6, CYP3A4 mRNA assays and the CYP3A (testosterone 6?-hydroxylation) and CYP2B6 (bupropion hydroxylation) enzyme activity assays. Bilobalide was not an antagonist of rPXR, hCAR, or hPXR, as suggested by the finding that it did not attenuate rPXR activation by pregnenolone 16?-carbonitrile, hCAR activation by 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime, or hPXR activation by rifampicin in reporter gene assays. In conclusion, bilobalide is an activator of rCAR, whereas it is not a ligand of rPXR, hCAR, or hPXR. Likewise, it is an inducer of rat CYP2B1, but not of rat CYP3A23, human CYP2B6, or human CYP3A4. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.
Source Title: Drug Metabolism and Disposition
ISSN: 0090-9556
DOI: 10.1124/dmd.111.042879
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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