In vitro studies of alcohol-induced liver injury in virally-infected human hepatocytes: Advantages and limitations

Abstract

Infection of liver with hepatotropic viruses is exacerbated by alcohol abuse. Toxic effects of alcohol on virally infected cells are induced not by alcohol per se, but by alcohol metabolism. To efficiently metabolize alcohol, cells should express ethanol-metabolizing enzymes, alcohol dehydrogenase (ADH) and cytochrome P450E1 (CYP2E1) that convert alcohol to acetaldehyde and generate reactive oxygen species (ROS). These enzymes are highly expressed in hepatocytes, making them the primary site of ethanol metabolism. All toxic effects of ethanol exposure to hepatocytes, which dose and time-dependently modulate viral replication, can be attributed to ethanol metabolism. Recently, we have shown that short-term exposure of HCV-infected cells to acetaldehyde enhances viral replication, while long-term exposure pushes cells to apoptosis [1, 2]. These effects were not observed if liver cells are unable to metabolize ethanol. Unfortunately, most of ethanol studies on HCVinfected and HBV-infected hepatocytes are performed on hepatoma cell lines (HepG2 and Huh7 cells), which serve as the surrogative in vitro hepatocyte models. Most of hepatoma cells do not express ADH and CYP2E1 and thus, are not affected by ethanol metabolism, making the obtained results questionable in terms of the effects of ethanol metabolism. Furthermore, human primary