Ethanol metabolism by macrophages: possible role in organ damage.

Abstract

Macrophages and hepatocytes oxidize ethanol to acetate in vitro at comparable rates but by different biochemical pathways. Ethanol metabolism by macrophages is largely ADH-independent and mainly based on cytochrome P450 and on the extracellular release of superoxide anion radicals. There is also evidence that during ethanol metabolism, macrophages release more acetaldehyde extracellularly than hepatocytes; the high concentrations of acetaldehyde around macrophages may damage surrounding tissue cells. Some of this acetaldehyde forms unstable cytotoxic complexes with serum albumin and with erythrocytes. The superoxide anion radicals released by macrophages may not only oxidize ethanol to acetaldehyde but also react with and damage cells in their immediate vicinity. After exposure to ethanol, macrophage-depleted rodents show markedly reduced levels of cytotoxic acetaldehyde-albumin complexes in the blood 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 activity. Macrophage-depleted animals also show less early liver damage than control animals. The reduction in ethanol-induced liver damage in macrophage-depleted mice and rats may be due to a reduction or elimination of the generation of various Kupffer-cell-derived hepatotoxic substances, including acetaldehyde and reactive oxygen radicals, in such animals. These data suggest that ethanol metabolism by tissue macrophages may play an important role in mediating ethanol-related tissue damage.