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Oxidative stress: A radical way to stop making bile

Marcelo G. Roma, Enrique J. Sánchez Pozzi

Abstract

Oxidative stress is a common feature in most hepatopathies. In recent years, evidence has accumulated that reactive oxygen species (ROS) induce a number of functional changes either deleterious or adaptive in the capability of the hepatocytes to produce bile and to secrete exogenous and endogenous compounds. This review is aimed to describe the mechanisms involved in these alterations. For this purpose, we will summarize: 1) The current evidence that acutely-induced oxidative stress is cholestatic, by describing the mechanisms underlying the hepatocyte secretory failure, including the disorganization of the actin cytoskeleton and its most noticeable consequences, the impairment of tight-junctional structures and the endocytic internalization of canalicular transporters relevant to bile formation. 2) The role for oxidative-stress-activated signalling pathways in the pathomechanisms described above, particularly those involving Ca2+ elevation and its consequent activation of Ca2+-dependent PKC isoforms. 3) The mechanisms involved in the adaptive response against oxidative stress mediated by ROS-responsive transcription factors, involving up-regulation of GSH-synthesizing enzymes, GSH-detoxifying enzymes and the hepatocellular efflux pumps; this response enhances the co-coordinated inactivation by GSH conjugation of lipid peroxides and their further cellular extrusion. 4) The manner this adaptive response can be surpassed by the sustained production of ROS, thus inducing transcriptional and posttranscriptional changes in transporters relevant to bile formation, as has been shown to occur, for example, after long-term administration of aluminum to rats, in the Long-Evans Cinnamon rat (a model of chronic hepatic copper accumulation mimicking Wilson's disease), and in ischemia-reperfusion injury.

Key words. Bile secretion, oxidative stress, calcium, signalling, cytoskeleton, transcription factor, canalicular transporters

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The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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