Acetaldehyde is highly toxic and can bind cellular constituents (e.g., proteins including CYP2E1, lipids, and nucleic acids) to produce harmful acetaldehyde adducts (Figure 5). Adduct formation changes
Figure 5 Formation of acetaldehyde adducts.
the structure and the biochemical properties of the affected molecules. The new structures may be recognized as foreign antigens by the immune system and initiate a damaging response.
Adduct formation leads to retention of protein within hepatocytes, contributing to the hepatomegaly, and several toxic manifestations, including impairment of antioxidant mechanisms (e.g., decreased glutathione (GSH)). Acetaldehyde thereby promotes free radical-mediated toxicity and lipid peroxidation. Binding of acetaldehyde with cysteine (one of the three amino acids that comprise GSH) and/or GSH also reduces liver GSH content. Chronic ethanol administration significantly increases rates of GSH turnover in rats. Acute ethanol administration inhibits GSH synthesis and increases losses from the liver. Furthermore, mitochondrial GSH is selectively depleted and this may contribute to the marked disruption of mitochondria in alcoholic cirrhosis.
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