Review PKC signaling in oxidative hepatic damage Mariapaola Nitti, Maria A. Pronzato, Umberto M. Marinari, Cinzia Domenicotti * Department of Experimental Medicine, General Pathology Section, L.B. Alberti 2, 16132 Genoa, Italy Received 2 August 2007; accepted 28 September 2007 Abstract Protein kinase C (PKC) is a family of isoenzymes differently involved in cell response to injury and many studies describe their role as ‘‘stress sensors’’. Oxidative stress is strictly involved in the pathogenesis of chronic liver diseases including alcohol- or drug-induced hepatotoxicity, iron overload, hepatitis and hepatocarcinoma development, but molec- ular mechanisms are not really defined. A crucial role of PKC as a redox sensitive signaling molecule has been widely accepted. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Protein kinase C; Liver; Oxidative stress; ROS; Ethanol Contents 1. Introduction ..................................................................... 37 2. Oxidative stress and hepatic damage .................................................... 37 2.1. Ethanol, oxidative stress and liver diseases............................................. 37 2.2. Cellular and molecular mechanisms leading to oxidative stress and liver damage .................. 37 2.3. Redox regulation of signal transduction .............................................. 38 3. PKC and oxidative stress ............................................................ 38 3.1. PKC family .................................................................. 38 3.2. PKC activation and oxidative modulation ............................................. 38 4. PKC and oxidative liver damage ....................................................... 39 5. Conclusions...................................................................... 40 0098-2997/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2007.09.001 Abbreviations: PKC, protein kinase C; ROS, reactive oxygen species; RNS, reactive nitrogen species; NO, nitric oxide; SOD, super- oxide dismutase; HCV, hepatitis C; ALD, alcohol-induced liver disease; GSH, glutathione; HCC, hepatocellular carcinoma; ADH, alcohol dehydrogenase; MEOS, microsomal ethanol oxidation system; H 2 O 2 , hydrogen peroxide; CYP2E1, cytochrome P4502E1; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde; HSCs, hepatic stellate cells; RTK, receptor tyrosine kinases; MAPK, mitogen-activated protein kinases; PI3-kinase phosphatidylinositol 3-kinase; EGF, epidermal growth factor; DAG, diacylglycerol; ERK, extracellular signal- regulated kinases; JNK, c-Jun N-terminal protein kinases; CCl 4 , carbon tetrachloride; BSO, buthionine sulfoximine; DEM, diethylmal- eate; TAA, thiocetamide; MCP-1, monocyte chemoattractant protein. * Corresponding author. Tel.: +39 0103538835; fax: +39 0103538836. E-mail address: cdomeni@medicina.unige.it (C. Domenicotti). Available online at www.sciencedirect.com Molecular Aspects of Medicine 29 (2008) 36–42 www.elsevier.com/locate/mam