Pathways of Ethanol Metabolism and Related Pathology

  • Charles S. Lieber
Part of the NATO ASI Series book series (NSSA, volume 206)


In ADH-mediated oxidation of ethanol, hydrogen is transferred from the substrate to the cofactor nicotinamide adenine dinucleotide (NAD), converting it to the reduced form (NADH) (Fig. 1). As a net result, ethanol oxidation by ADH generates an excess of reducing equivalents as free NADH in hepatic cytosol, primarily because the metabolic systems involved in NADH removal are not able to fully offset the accumulation of NADH. The acetaldehyde produced in this reaction is converted to acetate by aldehyde dehydrogenase, which is also associated with reduction of NAD to NADH. The large amounts of reducing equivalents produced overwhelm the hepatocyte’s ability to maintain redox homeostasis and a number of metabolic disorders ensue, including changes in protein, carbohydrate (hypoglycemia) and uric acid metabolism (Lieber, 1982). This redox mechanism also affects lipids: 1) ethanol oxidation provides reducing equivalents and two carbon units for lipid synthesis, 2) the more reduced redox state inhibits the oxidation of fatty acids and diverts them into esterification which is further enhanced by the increased concentration of sn-glycerol-3-phosphate, 3) ethanol affects the amount of fatty acids transported from the adipose tissue into the liver (Lieber et al., 1959; Lieber and Schmid, 1961; Lieber, 1982). A characteristic feature of liver injury in the alcoholic is the predominance of steatosis and other lesions in the perivenular (also called centrilobular) zone or zone 3 of the hepatic acinus. The mechanism for this zonal selectivity of the toxic effects involves several distinct and not mutually exclusive mechanisms: one hypothesis postulates that ethanol can produce hypoxic damage of perivenular hepatocytes whereas another postulates that relative hypoxic conditions normally prevailing in the perivenular zone enhance the metabolic toxicity of ethanol. Furthermore, the selective presence and induction of enzymes of alcohol metabolism in the perivenular zone is also contributory.


Alcohol Dehydrogenase Alcoholic Liver Disease Nicotinamide Adenine Dinucleotide Chronic Ethanol Alcoholic Hepatitis 
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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Charles S. Lieber
    • 1
  1. 1.Bronx VA Medical Center and Mount Sinai School of MedicineBronxUSA

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