Search results for "Androstane"
showing 10 items of 17 documents
Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy
2018
Hepatic induction in response to drugs and environmental chemicals affects drug therapies and energy metabolism. We investigated whether the induction is transmitted to the offspring. We injected 3-day- and 6-week-old F0 female mice with TCPOBOP, an activator of the nuclear receptor constitutive androstane receptor (CAR, NR1I3), and mated them 1-6 weeks afterward. We detected in the offspring long-lasting alterations of CAR-mediated drug disposition, energy metabolism, and lipid profile. The transmission to the first filial generation (F1) was mediated by TCPOBOP transfer from the F0 adipose tissue via milk, as revealed by embryo transfer, crossfostering experiments, and liquid chromatograp…
Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling
2020
The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXRLiver−/−) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis a…
Time-dependent changes in serum 3α-androstanediol glucuronide correlate with hirsutism scores after ovarian suppression
1995
The clinical utility of serum 3 alpha-androstanediol glucuronide level has been controversial. Among the concerns regarding its lack of utility has been the finding that suppression of serum 3 alpha-androstanediol glucuronide does not occur readily with treatment. We hypothesized that because the treatment of hirsutism requires a prolonged duration, a longer observation period is required for changes in serum 3 alpha-androstanediol glucuronide to be measured. Therefore, we studied the clinical and hormonal changes in 11 women treated for hirsutism with a gonadotropin-releasing hormone agonist (GnRH-a) for 1 year. A progressive reduction in Ferriman-Gallwey scores occurred, which was signifi…
Peripheral androgen blockade versus glandular androgen suppression in the treatment of hirsutism.
1991
Hirsutism in women is often explained on the basis of abnormal peripheral androgen metabolism. To determine whether serum markers of ovarian, adrenal, or peripheral androgen production may be helpful determinants in the treatment of hirsutism and to compare the efficacy of treatment with dexamethasone or spironolactone, 20 hyperandrogenic hirsute patients were treated for up to 2 years. Eleven women who were selected on the basis of sensitivity to dexamethasone were treated with a daily dose of 0.37 mg dexamethasone and had androgen levels suppressed into the normal range. Although significant (P less than .05), Ferriman-Gallwey scores decreased only by 20%: 14.2 +/- 0.5 to 11.4 +/- 0.6. Ni…
Evolutionary History and Functional Characterization of the Amphibian Xenosensor CAR
2011
AbstractThe xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result of whole-genome duplications. CAR genes were subsequently lost from the fish lineage, but they are conserved in all taxa of land vertebrates. This contrasts with PXR, which is found in most fish species, whereas it is lost from Sauropsida (reptiles and birds) and plays a role unrelated to xenosensing in Xenopus. This role is fulfilled in Xenopus by CAR, which exhibits low basal activity a…
Coordinated induction of drug transporters and phase I and II metabolism in human liver slices
2008
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24 h with prototypical inducers: phenobarbital (PB) (50 mu M) for CAR, beta-naphthoflavone (BNF) (25 mu M) for AhR, and rifampicin (RIF) (10 mu M) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2136, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, …
CCAAT/Enhancer-binding Protein α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Synergistically Cooperate with Constitutive Androstane Receptor to…
2010
The transcription of tissue-specific and inducible genes is usually subject to the dynamic control of multiple activators. Dedifferentiated hepatic cell lines lose the expression of tissue-specific activators and many characteristic hepatic genes, such as drug-metabolizing cytochrome P450. Here we demonstrate that by combining adenoviral vectors for CCAAT/enhancer-binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), and constitutive androstane receptor, the CYP2B6 expression and inducibility by CITCO are restored in human hepatoma HepG2 cells at levels similar to those in cultured human hepatocytes. Moreover, several other phase I and II genes are simultaneously activated, whic…
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use…
2013
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in…
Effects of typical inducers on olfactory xenobiotic-metabolizing enzyme, transporter, and transcription factor expression in rats.
2010
International audience; Several xenobiotic-metabolizing enzymes (XMEs) have been identified in the olfactory mucosa (OM) of mammals. However, the molecular mechanisms underlying the regulation of these enzymes have been little explored. In particular, information on the expression of the transcriptional factors in this tissue is quite limited. The aim of the present study was to examine the impact of five typical inducers, Aroclor 1254, 3-methylcholanthrene, dexamethasone, phenobarbital, and ethoxyquin, on the activities and mRNA expression of several XMEs in the OM and in the liver of rats. We also evaluated the effects of these treatments on the mRNA expression of transcription factors an…
Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium
2021
Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 a…