Lecture 3.1a - Alcohol Metabolism and oxidative stress.pdf

Alcohol - ethanol: ◦Ethanol is a small molecule that is both lipid and water soluble. ◦Ethanol is practically insoluble in fats and oils ◦Transported by simple diffusion across the cell membrane ◦Ethanol distributes from the blood into all tissues and fluids in proportion to th...

Alcohol - ethanol: ◦Ethanol is a small molecule that is both lipid and water soluble. ◦Ethanol is practically insoluble in fats and oils ◦Transported by simple diffusion across the cell membrane ◦Ethanol distributes from the blood into all tissues and fluids in proportion to their relative content of water. ◦Women generally have a smaller volume of distribution for alcohol than men because of their higher percentage of body fat. ◦The equilibrium concentration of alcohol in a tissue depends on the relative water content, rate of blood flow and the mass of that tissue. Distribution of alcohol in the body: ◦A woman's body is composed of approximately 45-50% water, while a man's body is about 55-65% water. ◦The lower fluid volume in women results in higher concentrations of alcohol in the bloodstream compared to men. ‣ Less water content -> higher alcohol concentration ‣ BAC = blood alcohol concentration Alcohol absorption: ◦Alcohol is absorbed in the stomach and intestine tissues ◦Alcohol crosses biological membranes by simple passive diffusion - doesn't require transporters or energy ◦Peak blood alcohol levels are higher if ethanol is ingested as a single dose rather than several smaller doses ◦The presence of food in the stomach retards gastric emptying and thus will reduce the absorption of alcohol, the "don't drink on an empty stomach" concept. Alcohol metabolism: ◦Most (>90%) alcohol is metabolised by the liver ◦Remainder excreted passively in urine and on breath (10%) ◦Enzymes - alcohol dehydrogenase (ADH) and cytochrome P450 ◦Acetaldehyde is toxic. It is metabolised further by acetaldehyde dehydrogenases (ALDH), which converts acetaldehyde further into acetate. ◦Acetate is not toxic and it is converted to acetyl-CoA in the skeletal muscle.  ◦Approximately 10-20% of ingested ethanol is oxidised through cytochrome P450 enzymes in the endoplasmic reticulum (especially CYP2E1) ◦The isoenzyme that has the highest activity toward ethanol is called CYP2E1. ◦The affinity of CYP2E1 increases at higher concentrations of ethanol ◦CYP2E1 is inducible Alcohol metabolism - liver: Alcohol metabolism - liver damage: ◦Alcohol-induced liver disease is a common and sometimes fatal consequence of chronic ethanol abuse. ◦Forms of liver damage: fatty liver, alcohol-induced hepatitis and alcoholic cirrhosis. ◦Many of the toxic effects of chronic ethanol consumption result from accumulation of acetaldehyde. ‣ Changes in fatty acid metabolism ‣ Generation of free radicals ‣ Chronic loss of function Clinical presentation - liver damage: ◦Mechanisms of liver damage: ‣ Fatty liver - inhibition of fatty acid oxidation and stimulation of triacylglycerol synthesis -> more fat produced ‣ Alcoholic hepatitis - generation of free radicals from acetaldehyde ‣ Alcoholic cirrhosis - damage to hepatocytes characterised by fibrosis, abnormal blood flow and loss of liver function. Treatment of alcohol dependence: ◦Disulfiram is a drug used to support the treatment of alcohol use disorder (form of psychotherapy) by producing an acute sensitivity to ethanol. ‣ Inhibits aldehyde dehydrogenase, resulting in no acetate being produced, but accumulation of acetaldehyde (toxic) ◦Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. ◦Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms (hangover)