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Polybrominated diphenyl ether BDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car−/− and Pxr−/− mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor constitutive activated/androstane receptor (CAR). In mouse livers, CAR, not PXR, was responsible for Cyp2b10 mRNA induction by BDE-47. In human primary hepatocytes, BDE-47 was able to induce translocation of YFP-tagged human CAR from the cytoplasm to the nucleus andCYP2B6 and CYP3A4 mRNAs expressions. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) in luciferase-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human pregnane X receptor (PXR) was effectively activated by BDE-47 while mouse PXR was weakly activated in luciferase-reporter assays. Our results indicate that BDE-47 induces CYP genes through activation of human CAR in addition to the previously identified pathway through human PXR. [ABSTRACT FROM AUTHOR]

KCNK1, a member of the family of two-pore K+ ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (−2441/−2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1−/− male mice compared with those of Kcnk1+/+ males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1−/− mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice. [ABSTRACT FROM AUTHOR]

Aims Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature. Methods and results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death. Conclusion PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence. [ABSTRACT FROM AUTHOR]

Proposes the work of Jacques Ellul for reconceptualizing the relationship among the citizen, the media, and the state. Hegemony theory and its modern variants; Ellul's view that the modern state is the product of the invasion of technique throughout society; Role of the social critic.

The effect of acute volume overload was studied in 20 dogs, nine of which had undergone pericardiectomy. End-diastolic and end-systolic left ventricular volumes, as determined by biplane angiocardiography, were significantly higher, and the ejected fraction relatively lower in the pericardiectomized group. It is concluded that the pericardium prevents excessive left ventricular dilatation and impairment of the ventricular function during acute hypervolaemia. [ABSTRACT FROM PUBLISHER]