Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-d-glucuronide-induced cholestasis

Abstract

Estradiol-17beta-D-glucuronide (E(2)17G) induces immediate and profound but transient cholestasis in rats when administered as a single bolus dose. Here, we examined the consequence of sustained E(2)17G cholestasis and assessed the function and localization of the tight junctional proteins zonula occludens-1 (ZO-1) and occludin and of the canalicular transporter multidrug resistance-associated protein-2 (Mrp2). An initial dose of E(2)17G (15 mumol/kg iv) followed by five subsequent doses of 7.5 mumol/kg from 60 to 240 min induced a sustained 40-70% decrease in bile flow. Following their biliary retrograde administration, cholera toxin B subunit-FITC or horseradish peroxidase were detected at the sinusoidal domain, indicating opening of the paracellular route; this occurred as early as 15 min after the first dose as well as 15 min after the last dose of E(2)17G, but not following the administration of vehicle in controls. Localization of ZO-1 and occludin was only slightly affected under acute cholestatic conditions but was severely disrupted under sustained cholestasis, with their appearance suggesting a fragmented structure. Endocytic internalization of Mrp2 to the pericanalicular region was apparent 20 min after a single E(2)17G administration; however, Mrp2 was found more deeply internalized and partially redistributed to the basolateral membrane under sustained cholestasis. In conclusion, acute E(2)17G-induced cholestasis increased permeability of the tight junction, while sustained cholestasis provoked a significant redistribution of ZO-1, occludin, and Mrp2 in addition to increased permeability of the tight junction. Altered tight junction integrity likely contributes to impaired bile secretion and may be causally related to changes in Mrp2 localization.

Evaluation of hepatotoxicity and cholestasis in rats treated with EtOH extract of Fructus Psoraleae

“…While the elevation of CYP7A1 expression is possibly due to the ablation of FXR together with its negative feedback on bile acid synthesis. In this study, we observed remarkable down-regulation of FXR and elevated expression of CYP7A1, MRP2, MRP3 in EEFP-treated female groups, suggesting the endogenously accumulation of bile acids which is reflected by the increase of serum bile acids (Kast et al, 2002;Mottino et al, 2007;Rost et al, 1999Rost et al, , 2008.…”

Sequential Activation of Classic PKC and Estrogen Receptor α Is Involved in Estradiol 17ß-D-Glucuronide-Induced Cholestasis

“…After fixation, liver slices were incubated overnight with the specific antibodies to Abcb11, Abcc2, and occludin, and this was followed by 1 hour of incubation with the appropriate cyanine 2-conjugated or cyanine 3-conjugated donkey anti-IgG. Occludin staining was carried out to demarcate the limits of the canaliculi [7], [36]. All images were taken with a Nikon C1 Plus confocal laser scanning microscope.…”

Sex-Dependent Claudin-1 Expression in the Liver of Euthyroid and Hypothyroid Mice

“…Previous in vitro studies have shown that progesterone and estradiol influence TJ expression in a concentration-dependent manner in human vascular endothelial and human endometrial epithelial cells [6,29] . However, animal studies concentrated on TJ proteins, like occludin or ZO-1, and data of claudin-1 are almost entirely missing [3] . It is thought that claudin-1 could be regulated via different signal transduction pathways like MAPkinase or PI3ki-nase [9] ; however, the data are not consistent and it will be interesting to consider these pathways in the context of nongenomic TH action.…”

“…Autoimmune thyroiditis is the most common cause of hypothyroidism in humans, and a female preponderance in both autoimmune thyroid disease and hypothyroidism has long been known [1,2] . The incidence of developing hypothyroidism in the Western world ranges between 0.6 and 3.5 per 1,000 people [3] . In Europe women are 1.7-to 6.8-fold more frequently affected by hypothyroidism than men [1,2] .…”