NADPH oxidase-generated reactive oxygen species are involved in estradiol 17ß-d-glucuronide-induced cholestasis.

The endogenous metabolite of estradiol, estradiol 17ß-D-glucuronide (E17G), is considered the main responsible of the intrahepatic cholestasis of pregnancy. E17G alters the activity of canalicular transporters through a signaling pathway-dependent cellular internalization, phenomenon that was attributed to oxidative stress in different cholestatic conditions. However, there are no reports involving oxidative stress in E17G-induced cholestasis, representing this the aim of our work. Using polarized hepatocyte cultures, we showed that antioxidant compounds prevented E17G-induced Mrp2 activity alteration, being this alteration equally prevented by the NADPH oxidase (NOX) inhibitor apocynin. The model antioxidant N-acetyl-cysteine prevented, in isolated and perfused rat livers, E17G-induced impairment of bile flow and Mrp2 activity, thus confirming the participation of reactive oxygen species (ROS) in this cholestasis. In primary cultured hepatocytes, pretreatment with specific inhibitors of ERK1/2 and p38MAPK impeded E17G-induced ROS production; contrarily, NOX inhibition did not affect ERK1/2 and p38MAPK phosphorylation. Both, knockdown of p47phox by siRNA and preincubation with apocynin in sandwich-cultured rat hepatocytes significantly prevented E17G-induced internalization of Mrp2, suggesting a crucial role for NOX in this phenomenon. Concluding, E17G-induced cholestasis is partially mediated by NOX-generated ROS through internalization of canalicular transporters like Mrp2, being ERK1/2 and p38MAPK necessary for NOX activation.

UDCA for Drug-Induced Liver Disease: Clinical and Pathophysiological Basis.

Drug-induced liver injury (DILI) is an adverse reaction to medications and other xenobiotics that leads to liver dysfunction. Based on differential clinical patterns of injury, DILI is classified into hepatocellular, cholestatic, and mixed types; although hepatocellular DILI is associated with inflammation, necrosis, and apoptosis, cholestatic DILI is associated with bile plugs and bile duct paucity. Ursodeoxycholic acid (UDCA) has been empirically used as a supportive drug mainly in cholestatic DILI, but both curative and prophylactic beneficial effects have been observed for hepatocellular DILI as well, according to preliminary clinical studies. This could reflect the fact that UDCA has a plethora of beneficial effects potentially useful to treat the wide range of injuries with different etiologies and pathomechanisms occurring in both types of DILI, including anticholestatic, antioxidant, anti-inflammatory, antiapoptotic, antinecrotic, mitoprotective, endoplasmic reticulum stress alleviating, and immunomodulatory properties. In this review, a revision of the literature has been performed to evaluate the efficacy of UDCA across the whole DILI spectrum, and these findings were associated with the multiple mechanisms of UDCA hepatoprotection. This should help better rationalize and systematize the use of this versatile and safe hepatoprotector in each type of DILI scenarios.

Application of green seaweed biomass for MoVI sorption from contaminated waters. Kinetic, thermodynamic and continuous sorption studies.

Spongomorpha pacifica biomass was evaluated as a new sorbent for Mo(VI) removal from aqueous solution. The maximum sorption capacity was found to be 1.28×10(6)±1×10(4) mg kg(-1) at 20°C and pH 2.0. Sorption kinetics and equilibrium studies followed pseudo-first order and Langmuir adsorption isotherm models, respectively. FTIR analysis revealed that carboxyl and hydroxyl groups were mainly responsible for the sorption of Mo(VI). SEM images show that morphological changes occur at the biomass surface after Mo(VI) sorption. Activation parameters and mean free energies obtained with Dubinin-Radushkevich isotherm model demonstrate that the mechanism of sorption process was chemical sorption. Thermodynamic parameters demonstrate that the sorption process was spontaneous, endothermic and the driven force was entropic. The isosteric heat of sorption decreases with surface loading, indicating that S. pacifica has an energetically non-homogeneous surface. Experimental breakthrough curves were simulated by Thomas and modified dose-response models. The bed depth service time (BDST) model was employed to scale-up the continuous sorption experiments. The critical bed depth, Z0 was determined to be 1.7 cm. S.pacifica biomass showed to be a good sorbent for Mo(VI) and it can be used in continuous treatment of effluent polluted with molybdate ions.