METABOLISM OF ALCOHOL AND REGULATIONS.pptx

Describes metabolism of alcohol, and regulation

1. Alcohol Metabolism KAWALYA STEVEN

2. Alcohol (ethanol or ethyl alcohol) is readily absorbed by the stomach & intestine. Only 1% of the alcohol consumed is excreted through lungs, urine & sweat . Major fraction of the alcohol is oxidized in liver . Alcohol gets oxidized in the liver by alcohol dehydrogenase to acetaldehyde.

3. Alcohol Dehydrogenase (ADH) It is an NAD + dependent cytoplasmic enzyme. It oxidizes ethanol to acetaldehyde. ADH is a dimer & has 6 isoenzymes . In some individuals the enzyme is mutated . In such individuals, alcohol metabolism is slower & even small quantity of alcohol may produce symptoms of intoxication.

4. ALdehyde Dehydrogenase Acetaldehyde is further oxidized to acetate by a mitochondrial NAD + dependent enzyme The acetate is then converted to acetyl CoA. The activity of ADH is more than aldehyde dehydrogenase (*ALDH). Acetaldehyde accumulates in liver. Aldehyde is toxic, excess may lead to cell death.

5. Alcohol Metabolism CH3-CH2-OH Ethanol CH3-CHO Acetaldehyde CH3-CHO Acetaldehyde CH3-COOH Acetic acid NAD + NADH+H + NAD + NADH+H + Alcohol Dehydrogenase Aldehyde Dehydrogenase

6. Microsomal Ethanol Oxidizing System ( MEOS) It is another mechanism of detoxification of alcohol. It is cytochrome P450 dependent & is inducible . Ethanol can be oxidized in liver microsomes to acetaldehyde by a mixed function oxidase. The electron donors are ethanol & NADPH by which O2 is reduced to water.

7. MEOS is part of the superfamily of cytochrome P450, all of which catalyze similar reactions. About 10 gene families & 100 different cytochrome P450 molecules are available . The isoenzyme with highest activity towards ethanol is designated CYP2E1 (2 refers to the gene family, E refers to the subfamily & 1 refers to the particular enzyme).

8. Absorption And KINETICS OF ALCOHOL ELIMINATION First pass effect by ADH; occurs in stomach Alcohol has irritant properties and high concentrations cause superficial erosions, hemorrhages and paralysis f stomach smooth muscle. zero-order process, meaning that alcohol is removed from the body at a constant rate , independent of the concentration of alcohol

9. Biochemical Alterations in Alcoholism The metabolism of alcohol (by both dehydrogenases ) involves the consumption of NAD + & consequently a high NADH/NAD + ratio . This is mostly responsible for the metabolic alterations observed in alcoholism.

10. Lactic acidosis: High concentration of NADH favours , the conversion of pyruvate to lactate, ↑ blood lactate concn , which may lead to metabolic lactic acidosis . Hypoglycemia : Alocohol oxidation raises NADH, inhibits key regulatory enzymes in gluconeogenesis, blocks formation and release of glucose from liver Deficiency of pyruvate leads to inadequate conversion of malate to formation of oxaloacetate. This results in depression of gluconeogenesis, leading to hypoglycemia

11. A Alcohol pancreatic microcirculation evokes massive redistribution of pancreatic blood flow from exocrine into endocrine (insulin producing), These are mediated by vagas nerve by NO as second messenger Hence augmenting late phase insulin secretion leading to hypoglyceamia

12. Alcohol hypoglycemia and ketosis Lypolitic and ketogenic path ways help to maintain glcose levels via gluconeogeneis , due to prolonged fasting and excess alcohol Ethanol cause structural abnormalities in mitochondria leading to ketosis Increased NADH in oxidation favors accumulation of hydroxyl butyrate

13. Reduced oxaloacetate, decreased pyruvate & high NADH, causes suppression of TCA cycle. Acetyl CoA is accumulated , which favors ketogenesis . Increased level of acetyl CoA causes increased fatty acid synthesis; but fatty acid is not oxidized . Fat is accumulated in liver , resulting in fatty liver.

14. Increased concentration of serum uric acid due to its reduced excretion is observed in alcoholism . This is due to lactic acidosis . Alcohol causes CNS depression by inhibiting excitatory receptors (N-methyl aspartate receptors ) & by potentiating inhibitory neurotransmitter (GABA) receptors.

15. Effects of Chronic Alcoholism Alcoholism and liver: Accumulation of fat in liver cells leading to fatty liver . Accumulated toxic effect of acetaldehyde leads to cellular death & replacement by fibrous tissue . Fibrosis of liver is called Cirrhosis . When liver functions are reduced hepatic coma results .

16. Alcoholism and Nervous Systes : In chronic alcoholics, the brain ventricles are enlarged , neurons are lost, neuro -degenerative changes. In alcoholics , combined thiamine deficiency leads to Wernick's disease . Aldehyde inhibits pyridoxal phosphate ; neuritis is very common in alcoholics.

17. Alcohol & Cardiovascular System : Mild alcohol intake (red wine less than 20 mg per day) will marginally elevate HDL & reduce the risk for myocardial infarction to a certain extent . A small percent of alcohol is eliminated through lungs. Lungs also share the deleterious effects of alcohol.

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