Question

Explain the toxic effects of excessive ethanol consumption on metabolism. In your answer, explain both the toxicity of ethanol metabolites at a molecular level and the specific effects of ethanol degradation on the major pathways we have studied (e.g., glycolysis, Krebs cycle, and the pentose phosphate pathway, to name a few).

Answer 1

Metabolic effects of alcohol and alcohol dependence

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Ethanol metabolism: factors influencing alcohol catabolism are rate of alcohol absorption, concentration and activity of liver ADH and aldehyde dehydrogenase (ALDH), and ratio of reduced to oxidized nicotinamide adenine dinucleotide (NADH/NAD+) in liver mitochondria. Availability and regeneration of NAD+ are rate-limiting factors for alcohol oxidation. Alcohol is converted to acetaldehyde by ADH, with cofactor NAD+. Aldehyde is responsible for harmful effects and addictive process; high blood aldehyde found in alcoholics and relatives after alcohol consumption—either increased ADH activity or depressed ALDH activity in people susceptible to alcohol dependence. Acetaldehyde is converted by ALDH to acetate, with little entering Krebs cycle; most is converted to long-chain fatty acids, leading to fatty liver.

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Fatty liver: in all alcoholics, even with minimal consumption; severity proportional to duration and degree of alcohol excess. Pathogenesis arises from increased endogenous fatty acid synthesis, diminished triglyceride utilization, impaired lipoprotein excretion, direct damage to endoplasmic reticula by free radicals produced by ethanol metabolism, and high-fat diet typical of alcoholics. Leptin is peptide hormone helping regulate appetite and energy metabolism. Circulating leptin levels are increased in a dose-dependent manner in chronic alcohol dependence regardless of nutritional status. Elevated leptin contributes to liver pathology: increased fibrosis, a known factor in liver steatosis.

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Hypoglycemia: alcohol induces reactive hypoglycemia and produces craving for foods that quickly elevate blood sugar (sugar and alcohol). Sugar aggravates reactive hypoglycemia, particularly with alcohol-induced impairment of gluconeogenesis. Hypoglycemia aggravates mental and emotional problems of alcoholics and withdrawal with sweating, tremor, tachycardia, anxiety, hunger, dizziness, headache, visual disturbance, decreased mental acuity, confusion, depression.

•             The equilibrium concentration of alcohol in a tissue depends on the relative water content of that tissue.

•             The rate of alcohol absorption depends on the rate of gastric emptying, the concentration of alcohol and is more rapid in the fasted state.

•             The blood alcohol concentration is determined by the amount of alcohol consumed,the presence or absence of food and the rate of alcohol metabolism.

•             First pass metabolism of alcohol occurs in the stomach and is decreased in alcoholics.

•             Liver alcohol dehydrogenase is the major enzyme system for metabolizing alcohol; this requires the cofactor NAD and the products produced are acetaldehyde and NADH.

•             The acetaldehyde is further oxidized to acetate, the same final metabolite produced from all other nutrients-carbohydrates, fats and proteins; the acetate can be converted to CO2, fatty acids, ketone bodies, cholesterol and steroids.

•             Oxidation of alcohol by cytochrome P450 pathways, especially CYP2E1 which is induced by alcohol, are secondary pathways to remove alcohol especially at high concentrations.

•             Alcohol metabolism is regulated by the nutritional state, the concentration of alcohol,specific isoforms of alcohol dehyrogenase, need to remove acetaldehyde and regenerate NAD and induction of CYP2E1.

•             Substrate shuttles and the mitochondrial respiratory chain are required to regenerate NAD from NADH, and this can limit the overall rate of alcohol metabolism.

•             Metabolism of alcohol is increased in alcoholics without liver disease: this metabolic tolerance to alcohol may involve induction of CYP2E1, elevated regeneration of NAD or endotoxemia.