Chapter 33: Metabolism of Ethanol

Ethanol metabolism represents a critical biochemical pathway with significant clinical consequences for human health. The liver is the primary site of ethanol processing, where alcohol dehydrogenase catalyzes the initial conversion to acetaldehyde, followed by acetaldehyde dehydrogenase conversion to acetate, both steps generating substantial amounts of NADH. At elevated ethanol concentrations, the microsomal ethanol-oxidizing system, particularly the cytochrome P450 enzyme CYP2E1, becomes increasingly active and generates reactive oxygen species that contribute to cellular damage and oxidative stress. The acetate product enters circulation and is activated to acetyl-CoA in peripheral tissues for energy production through the tricarboxylic acid cycle. The elevated hepatic NADH to NAD+ ratio resulting from ethanol oxidation creates a metabolic bottleneck that suppresses fatty acid oxidation, impairs gluconeogenesis, inhibits the citric acid cycle, and promotes lactate accumulation, collectively manifesting as acute metabolic complications including hypoglycemia, lactic acidosis, hyperuricemia, and ketoacidosis. Chronic ethanol consumption produces progressive liver pathology beginning with hepatic steatosis, advancing through alcoholic hepatitis, fibrosis, and ultimately irreversible cirrhosis driven by acetaldehyde toxicity and continuous oxidative injury. Hepatic fibrosis develops through stellate cell activation mediated by Kupffer cell signaling and transforming growth factor beta-1 release, leading to excessive collagen deposition and architectural distortion. Genetic polymorphisms in the alcohol-metabolizing enzymes influence individual susceptibility to alcoholism and liver disease risk. Clinical applications include disulfiram therapy, which inhibits acetaldehyde dehydrogenase to create an aversive reaction, and recognition that chronic alcohol consumption induces CYP2E1 expression, altering drug metabolism and increasing hepatotoxicity risk. Although ethanol provides approximately seven kilocalories per gram, chronic consumption reduces ATP yield efficiency through increased MEOS activity and mitochondrial dysfunction, explaining the nutritionally bankrupt nature of alcohol calories.