Hepatocellular metabolism of 4-hydroxy-2,3-nonenal is impaired in conditions of chronic cholestasis

4-Hydroxy-2,3-nonenal is a major aldehydic end-product of lipid peroxidation known to exert several biological and cytotoxic effects and to be produced during conditions of chronic cholestasis. Here we report that viable hepatocytes isolated from cholestatic livers of bile duct-ligated rats (BDL hepatocytes) show a significantly lower rate of HNE metabolism than control cells. This feature is likely to be the consequence of a significant inhibition in the activity of HNE-metabolizing cytosolic glutathione-S-transferase and alcohol dehydrogenase in BDL hepatocytes. Particulate NADP-dependent aldehyde dehydrogenase was also inhibited. No significant change was found for aldehyde reductase activity. A decreased hepatocellular metabolism of HNE can expose liver parenchymal and non-parenchymal cells to cytotoxic as well as pro-inflammatory and pro-fibrogenic effects of HNE, contributing to the development of chronic cholestatic liver damage.