Species-Dependent and Receptor-Selective Action of Bilobalide on the Function of Constitutive Androstane Receptor and Pregnane X Receptor

Abstract

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.

Toxicity and Carcinogenicity Studies of Ginkgo biloba Extract in Rat and Mouse

“…Overexpression of gene profiles for cancer signaling pathways, xenobiotic metabolism, and oxidative stress was also observed in GBE-induced hepatocellular carcinomas (Hoenerhoff et al 2012). Findings in both studies are consistent with literature indicating that GBE, as well as several individual GBE constituents, can activate various receptors (e.g., CAR, PXR, AhR) involved in xenobiotic metabolizing enzyme induction (Lau et al 2012a; Lau et al 2012b; Lau et al 2010; Li et al 2009). …”

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

“…After 24 h of culture, fresh medium containing 1.0 or 10 μM GNT was added and cells were further incubated for 48 h. Cells were then rinsed and incubated with different concentrations of Sfb (0–200 μM) for 16 h. P-gp and MRP2 participation was confirmed coincubating the cells either with 10 μM PSC833 (P-gp inhibitor), with 10 μM MK571 (MRP2 inhibitor) or with PSC833 and MK571 (10 μM each). CYP3A4 participation in the modulation of Sfb cytotoxicity was assessed coincubating the cells with 1.0 μM ketoconazole (CYP3A4 inhibitor) [ 43 ]. Cell viability was then evaluated through the MTT assay as described [ 37 ].…”

Carboxylesterases: Pharmacological Inhibition Regulated Expression and Transcriptional Involvement of Nuclear Receptors and other Transcription Factors

“…In human primary hepatocytes or hepatic cell lines, rifampicin at 10 M efficaciously induce CES1 and CES2 [75]. In addition, rifampicin activates pregnane X receptor but not constitutive androstane receptor [104,105].…”