Implications of oxidative stress in pathogenesis of cholestasis.

ABSTRACT

Cholestasis results from both genetic and acquired conditions causing disordered bile secretion and flow resulting in accumulation of toxic cholephiles in the blood. Prolonged and unrelieved cholestasis leads to liver injury, fibrosis and failure. Recent advances in understanding of the molecular mechanism of cholestasis, including function of biliary transporters and their regulation, have provided significant insights into pathophysiological derangements in cholestasis. Oxidative stress, caused by unchecked and dysregulated accumulation of reactive oxygen species (ROS) has emerged as an important contributor to cholestatic liver injury. Adaptive mechanisms in the liver through participation of redox responsive transcription factors, mainly the Nfr2/Keap1 system, as well as NF-kB and AP-1 are important. Oxidative stress induced actin disorganization with tight-junction impairment and transporter internalization have been observed to occur along with activation of Ca2+ dependent protein kinase C isoforms (cPKCs) in cholestasis related oxidative stress, that plays an important role in secretory failure . Animal models of cholestasis have been developed and inflammation has been found to play a significant role in cholestasis induced liver injury. A complete understanding of the redox sensitive signaling pathways involved in cholestasis is very much essential in order to have a more complete picture for better insight into the selective therapeutic strategies to abrogate ROS mediated harmful pathways, or to enhance the protective ones.