Why is Understanding Pathways of Ethanol Metabolism Importat为什么对乙醇代谢的重要途径.ppt

Frequency of ADH Allelesin Racial Populations Bosron et. al. 1993 Crabb 1995 Metabolic Adaptation (Tolerance) Besides CNS adaptation, alcoholics (in the absence of liver disease) often display an increased rate of blood alcohol clearance. This is called metabolic tolerance or adaptation. Suggested mechanisms include: 1. Induction of ADH. 2. Increased shuttle capacity. 3. Increased reoxidation of NADH. 4. Induction of CYP2E1. 5. Release of cytokines or prostaglandins which increase oxygen consumption by the hepatocytes. Acetaldehyde Metabolism The balance between the various ADH and ALDH isoforms regulates the concentration of acetaldehyde, which is important as a key risk factor for the development of alcoholism. 1. Isoforms of ALDH (ALDH2*2 in asian populations). 2. Effects of Alcohol Consumption. 3. Alcohol-aversive drugs. 4. Significance of Acetaldehyde Removal. Some Suggested Causes for Alcohol Toxicity Redox state changes (↓NAD+/NADH) Acetaldehyde formation (liver, brain?) Mitochondrial damage Cytokine formation (liver) Kupffer cell activation (liver) Increased gut permeability to endotoxins (elevated cytokines and liver damage) Immune response Hypoxia Oxidative stress Excitotoxicity (brain) Vitamin Deficiency (thiamin, folate, brain) The Visible, and Possibly Intoxicated, Man EtOH actions on brain neurons, synapses and receptors produce intoxication, tolerance, dependence, addiction and neurotoxicity EtOH metabolized in liver by ADH and other enzymes. Toxic metabolites and other substances lead to hepato- toxicity, chirossis, and liver cancer. Stomach EtOH absorption and 1st-pass metabolism, affects pharmaco- kinetics. Influences liver toxicity. EtOH distributes throughout the body. Afffected by water content, blood flow, tissue mass. Blood Vessels Blood flow affects rate of EtOH distribution. Eye Methanol toxicity due to formaldehyde formation. Esophagus EtOH potentiation