ETHANOL-METABOLISM BY MACROPHAGES - POSSIBLE ROLE IN ORGAN DAMAGE

Macrophages and hepatocytes oxidize ethanol to acetate in vitro at com parable rates but by different biochemical pathways. Ethanol metabolis m by macrophages is largely ADH-independent and mainly based on cytoch rome P450 and on the extracellular release of superoxide anion radical s. There is also evidence that during ethanol metabolism, macrophages release more acetaldehyde extracellularly than hepatocytes; the high c oncentrations of acetaldehyde around macrophages may damage surroundin g tissue cells. Some of this acetaldehyde forms unstable cytotoxic com plexes with serum albumin and with erythrocytes. The superoxide anion radicals released by macrophages may not only oxidize ethanol to aceta ldehyde but also react with and damage cells in their immediate vicini ty. After exposure to ethanol, macrophage-depleted rodents show marked ly reduced levels of cytotoxic acetaldehyde-albumin complexes in the b lood and reduced levels of hydroxyethyl radicals in the bile compared to control animals, indicating that the generation of such potentially pathogenic molecules is, to a large extent, dependent on macrophage a ctivity. Macrophage-depleted animals also show less early liver damage than control animals. The reduction in ethanol-induced liver damage i n macrophage-depleted mice and rats may be due to a reduction or elimi nation of the generation of various Kupffer-cell-derived hepatotoxic s ubstances, including acetaldehyde and reactive oxygen radicals, in suc h animals. These data suggest that ethanol metabolism by tissue macrop hages may play an important role in mediating ethanol-related tissue d amage.