CYP2E1ADHCATALASEMitochondriaMicrosom sCytosolP roxisom sH2O2 CH3CH2OH Ethanol NADPH + H+ NADP+, H2O NAD+ NADH + H+ NAD+ NADH + H+ + O2 CH3C Acetaldehyde Acetic acid H2O H2O O H CH3C O OH CH3CH OH OH ALDH
Fig. 8.10 Metabolismofethanol:oxidationofethanoltoacetaldehydebythreedifferentroutes,andthegenerationofaceticacid.Notethatoxidationbyalcoholdehydrogenase(ADH)takesplaceinthecytosol;thecytochromeP-450systemanditsCYP2E1isoformarelocatedintheER(microsomes),andcatalaseislocatedinperoxisomes.Oxidationofacetaldehydebyaldehydedehydrogenase(ALDH)occursinmitochondria.(Data from Parkinson A: Biotransformation of xenobiotics. In Klassen CD, editor: CasarettandDoull’stoxicology:Thebasicscienceofpoisons,ed 6, New York, 2001, McGraw-Hill, pp 133.)
Acetaldehyde toxicity may be responsible for some of the acute effects of alcohol. Acetaldehyde metabolism differs between populations because of genetic variation. Most notably, about 50% of Asians express a defective form of acetaldehyde dehydrogenase. After ingesting alcohol, such persons experience flushing, tachycardia, and hyperventilation owing to the accumulation of acetaldehyde.
ROS generation. Metabolism of ethanol in the liver by CYP2E1 produces ROS and causes lipid peroxidation of cell membranes. Nevertheless, the precise mechanisms that account for alcohol-induced cellular injury have not been well defined.
Endotoxin release. Alcohol may cause the release of endotoxin (lipopolysaccharide), a product of gram-negative bacteria, from the intestinal flora. Endotoxin stimulates the release of tumor necrosis factor (TNF) and other cytokines from circulating macrophages and from Kupffer cells in the liver, causing cell injury.
Acute alcoholism exerts its effects mainly on the CNS but also may induce reversible hepatic and gastric injuries. Even with moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis). Gastric damage occurs in the form of acute gastritis and ulceration. In the CNS, alcohol is a depressant, first affecting subcortical structures that modulate cerebral cortical activity. Consequently there is stimulation and disordered cortical, motor, and intellectual behavior. At progressively higher blood levels, cortical neurons and then lower medullary centers are depressed, including those that regulate respiration. Respiratory arrest may follow.
Chronic alcoholism affects not only the liver and stomach but virtually all other organs and tissues as well. Chronic alcoholics suffer significant morbidity and have a shortened life span, related principally to damage to the liver, GI tract, CNS, cardiovascular system, and pancreas.
The liver is the main site of chronic injury. In addition to fatty change, mentioned earlier, chronic alcoholism causes alcoholic hepatitis and cirrhosis (described in Chapter 16). Cirrhosis is associated with portal hypertension and an increased risk of hepatocellular carcinoma.
In the GI tract, chronic alcoholism can cause massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may prove fatal.