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![Chemical structure of bilobalide. [The figure has been drawn on the basis of the findings in van Beek and Montoro, 2009.]](profile/Guixiang-Yang/publication/51735349/figure/fig1/AS:393906752638983@1470926096191/Chemical-structure-of-bilobalide-The-figure-has-been-drawn-on-the-basis-of-the-findings.png)
Chemical structure of bilobalide. [The figure has been drawn on the basis of the findings in van Beek and Montoro, 2009.]
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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 compare...
Citations
... 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]. ...
Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that determine the therapeutic efficacy and toxicity of ester/amide drugs. Without exceptions, all mammalian species studied express multiple forms of carboxylesterases. Two human carboxylesterases, CES1 and CES2, are major contributors to hydrolytic biotransformation. Recent studies have identified therapeutic agents that potently inhibit carboxylesterases-based catalysis. Some of them are reversible whereas others irreversible. The adrenergic antagonist carvedilol, for example, reversibly inhibits CES2 but this carboxylesterase is irreversibly inhibited by orlistat, a popular anti-obesity medicine. Kinetically, the inhibition occurs competitively, non-competitively or in combination, depending on a carboxylesterase. For example, the calcium channel blocker diltiazem competitively inhibits CES1 but non-competitively inhibits CES2. In addition to inhibited catalysis, several therapeutic agents or disease mediators have been shown to regulate the expression of carboxylesterases. For example, the antiepileptic drug phenobarbital induces both human and rodent carboxylesterases, whereas the antibiotic rifampicin induces human carboxylesterases only. Conversely, the proinflammatory cytokine interleukin-6 (IL-6) suppresses the expression of carboxylesterases across species, but depending on the concentrations of glucose in the culture medium. Transactivation, transrepression and altered mRNA stability contribute to the regulated expression. Several nuclear receptors are established to support the regulation including constitutive androstane receptor, glucocorticoid receptor and pregnane X receptor. In addition, non-ligand transcription factors are also involved in the regulation and exemplified by differentiated embryo chondrocyte-1, nuclear factor (erythroid-derived 2)-like 2 and tumor protein p53. These transcription factors coordinate the regulated expression of carboxylesterases, constituting a regulatory network for the hydrolytic biotransformation.
... Second, we wanted to build a bridge between previous and current animal studies and more human-relevant models. This was particularly important due to the species-dependent activity of the CAR pathway (Lau et al., 2012;Cherian et al., 2015), which has been implicated in GBE hepatotoxicity (Maeda et al., 2014(Maeda et al., , 2015. In vitro methods to compare various samples of the same botanical can be useful because they provide quick and human-relevant information (with the use of human cell lines), and they can be tailored to specific biological activities (e.g., CAR and PXR activity). ...
Botanical dietary supplements are complex mixtures with numerous potential sources of variation along the supply chain from raw plant material to the market. Approaches for determining sufficient similarity (i.e., complex mixture read-across) may be required to extrapolate efficacy or safety data from a tested sample to other products containing the botanical ingredient(s) of interest. In this work, screening-level approaches for generating both chemical and biological-response profiles were used to evaluate the similarity of black cohosh (Actaea racemosa) and Echinacea purpurea samples to well-characterized National Toxicology Program (NTP) test articles. Data from non-targeted chemical analyses and gene expression of toxicologically-important hepatic receptor pathways (AhR, CAR, PXR, FXR, and PPARα) in primary human hepatocyte cultures were used to determine similarity through hierarchical clustering. Although there were differences in chemical profiles across black cohosh samples, these differences were not reflected in the biological-response profiles. These findings highlight the complexity of biological-response dynamics that may not be reflected in chemical composition profiles. Thus, biological-response data could be used as the primary basis for determining similarity among black cohosh samples. Samples of Echinacea purpurea displayed better correlation in similarity across chemical and biological-response measures. The general approaches described herein can be applied to complex mixtures with unidentified active constituents to determine when data from a tested mixture (e.g., NTP test article) can be used for hazard identification of sufficiently similar mixtures, with the knowledge of toxicological targets informing assay selection when possible.
... Second, we wanted to build a bridge between previous and current animal studies and more human-relevant models. This was particularly important due to the species-dependent activity of the CAR pathway (Lau et al., 2012;Cherian et al., 2015), which has been implicated in GBE hepatotoxicity (Maeda et al., 2014(Maeda et al., , 2015. In vitro methods to compare various samples of the same botanical can be useful because they provide quick and human-relevant information (with the use of human cell lines), and they can be tailored to specific biological activities (e.g., CAR and PXR activity). ...
Botanical dietary supplements are complex mixtures that can be highly variable in composition and quality, making safety evaluation difficult. A key challenge is determining how diverse products in the marketplace relate to chemically and toxicologically characterized reference samples (i.e., how similar must a product be in order to be well-represented by the tested reference sample?). Ginkgo biloba extract (GBE) was used as a case study to develop and evaluate approaches for determining sufficient similarity. Multiple GBE extracts were evaluated for chemical and biological-response similarity. Chemical similarity was assessed using untargeted and targeted chemistry approaches. Biological similarity was evaluated using in vitro liver models and short-term rodent studies. Statistical and data visualization methods were then used to make decisions about the similarity of products to the reference sample. A majority of the 26 GBE samples tested (62%) were consistently determined to be sufficiently similar to the reference sample, while 27% were different from the reference GBE, and 12% were either similar or different depending on the method used. This case study demonstrated that approaches to evaluate sufficient similarity allow for critical evaluation of complex mixtures so that safety data from the tested reference can be applied to untested materials.
... In contrast to classical steroid hormone receptors, CAR and PXR display very large species differences in the LBD sequences (Reschly & Krasowski, 2006), resulting in different profiles of compounds that can activate human and rodent receptors (Jyrkkärinne et al., 2005;Lau et al., 2012;Shukla et al., 2011;Vignati et al., 2004). In some cases, amino acids responsible for these human/rodent differences of select ligands have been identified (Jyrkkärinne et al., 2003(Jyrkkärinne et al., , 2005Ö stberg et al., 2002;Tirona et al., 2004;Watkins et al., 2001). ...
1. Nuclear receptors CAR (NR1I3) and PXR (NR1I2) are major ligand-activated transcriptional regulators of xenobiotic metabolism and disposition and modulators of endobiotic metabolism. Differences in xenobiotic selectivity between the human and rodent receptors are well recognized but there is lack of such information on properties of CAR and PXR in important domestic animals. 2. The pig and bovine receptors were cloned and their ligand profiles were systematically compared to corresponding human and mouse forms utilizing a panel of xenobiotics and structural analysis. 3. Pig CAR and PXR resemble their human counterparts which can be rationalized by only modest amino acid changes between critical residues of the human ligand-binding pockets (H203Q for CAR, L210V and M243I for PXR). 4. In contrast, bovine CAR shows a blunted response to CAR agonists and inverse agonists. These changes are likely due to disruptive mutations at or near critical hydrogen bond-forming residues (N165I, Y326F). The unresponsiveness of bovine PXR to human- and mouse-selective agonists may be related to substitutions at important ligand-contacting residues R410Q and F305V, respectively. 5. Our findings have implications for regulation of drug-metabolizing enzymes and transporters and pharmacokinetics in cattle and pigs.
... Ellagic acid, Resveratrol [153] H,M No PXR activity Activates hCAR better than mCAR Terpenoid Squalestatin-1 [154] R Terpenoid Bilobalide [148,155] [157][158][159] H, M Strong PXR activator Insecticide Dieldrin [138] M Activates PXR Insecticide Methoxychlor [160][161][162] H, M Activates PXR Insecticide Metofluthrin [104] R Insecticide Permethrin [159,163] H Activates PXR Insecticide Pyrethrins [164] R Activates PXR Insecticide Sulfoxaflor [165] M, R Activates PXR Plasticizer ...
Introduction:
The constitutive androstane receptor (CAR) induces drug-metabolizing enzymes for xenobiotic metabolism.
Areas covered:
This review covers recent advances in elucidating the biological functions of CAR and its modulation by a growing number of agonists and inhibitors.
Expert opinion:
Extrapolation of animal CAR function to that of humans should be carefully scrutinized, particularly when rodents are used in evaluating the metabolic profile and carcinogenic properties of clinical drugs and environmental chemicals. Continuous efforts are needed to discover novel CAR inhibitors, with extensive understanding of their inhibitory mechanism, species selectivity, and discriminating power against other xenobiotic sensors.
... The dose-related increase in Ctnnb1 gene mutations in GBE-treated carcinomas was accompanied by an increase in posttranslational protein modification of CTNNB1. 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 (Lau, Yang, Rajaraman, et al. 2012;Lau, Yang, Yap, et al. 2012;Lau et al. 2010;Li et al. 2009). ...
Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, 3-month and 2-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use.
... PXR is primarily expressed in the hepatic tissues and to lower extent in other non-hepatic tissues both in human and in mice [5]. Despite the fact that human PXR and mouse PXR gene transcriptionally respond to important physiologic stimuli and therapeutic drugs [3,6], till date reports examining regulatory mechanisms that govern PXR gene expression in these cells remain relatively unexplored. A few studies done earlier on characterizing the DNA sequences involved in regulating PXR gene expression focused on the mouse PXR gene [7,8] but subsequent studies on human PXR gene revealed complexities involved in PXR gene regulation91011. ...
Pregnane X Receptor (PXR) is an important ligand-activated nuclear receptor functioning as a 'master regulator' of expression of phase I, phase II drug metabolizing enzymes, and members of the drug transporters. PXR is primarily expressed in hepatic tissues and to lesser extent in other non-hepatic tissues both in human and in mice. Although its expression profile is well studied but little is known about the regulatory mechanisms that govern PXR gene expression in these cells. In the present study, we have cloned and characterized over 5 kb (-4963 to +54) region lying upstream of mouse PXR transcription start site. Promoter-reporter assays revealed that the proximal promoter region of up to 1 kb is sufficient to support the expression of PXR in the mouse liver cell lines. It was evident that the 500 bp proximal promoter region contains active binding sites for Ets, Tcf, Ikarose and nuclear factor families of transcription factors. Electrophoretic mobility shift assays demonstrated that the minimal region of 134 bp PXR promoter was able to bind Ets-1 and β-catenin proteins. This result was further confirmed by chromatin immunoprecipitation analysis. In summary, the present study identified a promoter region of mouse PXR gene and the transregulatory factors responsible for PXR promoter activity. The results presented herein are expected to provide important cues to gain further insight into the regulatory mechanisms of PXR function.
Scientists from Canadian institutions have a rich history of making interesting and important contributions to the journal Drug Metabolism and Disposition (DMD) over the past 51 years. A goal of this minireview is to highlight these contributions and pay tribute to many of the scientists at Canadian institutions that have aided in the evolution of the discipline through their DMD publications. We conducted a geographical and research sectoral analysis of the temporal trends of DMD publications originating from Canadian sources. The fraction of total DMD papers of Canadian origin achieved a peak during the 1990s and since that time, this metric has displayed a pronounced and steady decline to the present situation, where the country needs to be concerned about its potentially vulnerable global status within the realm of drug metabolism and disposition science. Stronger and timely investment by Canadian academic institutions in drug metabolism and disposition science may help to restore the nation's research excellence in this discipline and ensure a more robust pipeline of appropriately trained scientists to take on careers in academia, industry, and government. Significance Statement The substantial contributions made by scientists at Canadian institutions to the journal Drug Metabolism and Disposition (DMD) are highlighted and celebrated in this minireview. Analysis of temporal trends in the fraction of total DMD papers of Canadian origin paints a concerning picture of Canada's current global status in the realm of drug metabolism and disposition science. Further investment in this discipline at Canadian universities may be needed.
Bilobalide is a natural sesquiterpene trilactone from Ginkgo biloba leaves. It has good water solubility and is widely used in food and pharmaceutical fields. In the last decade, a plethora of studies on the pharmacological activities of bilobalide has been conducted and demonstrated that bilobalide possessed an extensive range of pharmacological activities such as neuroprotective, antioxidative, antiinflammatory, anti‐ischemic, and cardiovascular protective activities. Pharmacokinetic studies indicated that bilobalide may have the characteristics of rapid absorption, good bioavailability, wide distribution, and slow elimination. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and safety studies of bilobalide in the last decade with an emphasis on its neuroprotective and antiinflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.
Aim: To observe the effects of rat specific PXR activator dexamethasone (DEX) on isoniazid (INH)-induced hepatotoxicity and investigate the mechanism, in order to provide theoretical basis for clinical strategies against anti-tuberculosis drug-induced liver injury. Methods: Male SD rats were randomly divided into four groups (n = 6) : Control, DEX, INH and DEX-INH group. Rats were fed a DEX-containing diet (20 mg·kg-1, W/W) and INH-containing water (1000 mg·L-1, W/V) respectively. Hepatotoxicity was evaluated 4 weeks after the treatment by histological chemistry. The activity of CYP3A in hepatic tissues, the serum ALT, AST, ALP and lipids level were determined. Results: Rat liver index increased significantly in the groups which were fed diet containing DEX. CYP3A activity in DEX-INH group increased nearly threefold compared with the control group. The histological detection showed fatty degeneration and piecemeal necrosis occurred in DEX-INH group. There was a significant difference between INH group and DEX-INH group in the serum ALT, AST, ALP and TC level (P < 0.01). Conclusion: Rat PXR activator DEX can exacerbate INH-induced liver injury. Its mechanism may be related to up-regulation of CYP3A activity by DEX.
