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https://doi.org/10.1124/dmd.111.042879
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 bilobalide 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 rifampicin unclassified drug animal cell article concentration response controlled study drug mechanism enzyme activation enzyme activity gene expression gene location gene targeting human human cell hydroxylation liver cell nonhuman nucleotide sequence priority journal protein function protein localization protein targeting rat reporter gene Animals Cell Line, Tumor Cells, Cultured Cyclopentanes Furans Ginkgolides Hep G2 Cells Hepatocytes Humans Rats 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. https://doi.org/10.1124/dmd.111.042879 | 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 | URI: | https://scholarbank.nus.edu.sg/handle/10635/183910 | ISSN: | 0090-9556 | DOI: | 10.1124/dmd.111.042879 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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