Chapter 68: Ethanol Metabolism Flashcards
Functional definition of alcoholism
- Consumption of alcohol to the point where normal social, sexual or vocational functioning is significantly impaired
- Usually 50% of caloric intake is in the form of alcohol
Quantitative definition of alcoholism (WHO)
- Daily consumption of more than 120 grams (4.2 oz.) of pure alcohol per day
Ethanol absorption
- Rapidly and without modification
- 20% stomach, 80% in intestines
Blood alcohol content
- Detectable within five minutes of consumption
- Peaks in 30 to 45 minutes
Blood alcohol concentration curve
- Estimates time needed to absorb and metabolize alcohol
After absorption alcohol is distributed to the tissues of the body
- Direct proportion to blood flow
- Small amount not metabolized (excreted via sweat, saliva, urine, breath)
- None is stored
BAC vs. time
- 100 mg/dL = legal intoxication
- 50 mg/dL = driving impaired
Alcohol metabolism rates
- Metabolized slower than absorbed
- Accumulation = intoxication
Oxidative breakdown of alcohol
- Occurs in liver
- Broken down to acetaldehyde (via ADh) –> acetate + acetyl CoA –> CO2 + H2O (via the CAC)
Ethanol (alcohol) is metabolized by
- Catalase
- Cytochrome P450
- Alcohol dehydrogenase
First pass metabolism of alcohol is reduced by
- Aspirin
- Cimetidine
- Ranitidine
Ethanol metabolism generates
- NADH
- Inhibits gluconeogenesis + FA metabolism
Gluconeogenic/FA metabolism enzymes inhibited by NADH from ethanol metabolism
- Pyruvate carboxylase
- Malate dehydrogenase
NADH produced from the oxidation of ethanol can be used to
- Generate ATP
- Fat deposits observed in the liver (even after one night)
- Liver develops a decreased capacity to burn fat
Excess NADH shifts the equilibrium of
- Lactate dehydrogenase reaction
- Accumulation of lactate predisposes to gout
Minor pathway of alcohol metabolism
- Isoenzymes of microsomal enzyme cytochrome P 450 (CYP2EI)
Isoenzymes of cytochrome P 450 (CYP2EI)
- May be increased after chronic drinking
- Important in accelerated ethanol metabolism (associated with tolerance)
Small quantity of alcohol that remains unmetabolized permits
- Measurement of alcohol concentration in breath and urine
Food influences alcohol
- More dietary fat = longer absorption
Age influences alcohol
- Older = less body water, loss of muscle tissue, decreased metabolism
Gender influences alcohol
- Women = higher BACs
- Less body water (and higher body fat) = concentrates alcohol
- Lower activity of gastric/liver alcohol dehydrogenase
Body weight influences alcohol
- Doesn’t always result in increased body weight (despite 7.1 kcal/g high caloric value)
Medication influences alcohol
- Chronic heavy drinking = activates cytochrome P450
- Acetaminophen pain relievers (e.g Tylenol) can increase risk of kidney/liver disease
Short term alcohol related damage
- Inhibition of microsomal hydroxylase system
- CNS effects (sociability & elation)
- Hepatic effects (fat deposition/steatosis, necrosis
- Mitochondrial swelling
Long term alcohol related damage
- Induction of cytochrome P450 system
- Excess NADH production and NAD utilization
- Alcoholic hepatitis (acute or chronic; may be reversible)
- Increases susceptibility of liver to other drugs
Long term effects of excess NADH production and NAD utilization
- Inhibition of gluconeogenesis
- Alcohol-induced hypoglycemia
Alcohol decreases synthesis of liver proteins, causing
- Extended prothrombin time (blood thinning)
Alcohol decreases hepatic activation of
- Vitamins
Acetaldehyde effects due to alcohol consumption
- Carcinogenic
- Released into the blood, so effects are widespread
Chronic alcoholism in men can cause
- Gynecomastia
- Hypotrophy of testes
Cirrhosis
- Replacement of liver tissue with fibrous tissue
- Causes irreversible loss of liver function
- 10-15% of alcoholics have cirrhosis at time of death
Production of cirrhosis
- Takes 5-25 years of heavy drinking
- Recall that AST/ALT ratio > 2 in alcoholic liver disease
Cirrhosis symptom development
- About 60% of liver tissue can be destroyed before symptoms appear
Common symptoms of cirrhosis
- Jaundice
- Ascites
- Edema
Portal hypertension as a result of cirrhosis
- Due to fibrotic build up, blood flow through the liver is impeded
- Causes formation of esophageal varices
Portal hypertension may be worsened by
- Inadequate prothrombin production by the liver
- Contributes to bleeding esophageal varices common in alcoholics
“Advantages” of light alcohol ingestion
- Potential reduced incidence of heart disease
- Increasing HDL circulating levels (“good” cholesterol)
- Antioxidant effects of various compounds
- Antioxidant potential
Heme-containing cytochrome P450 2E1 (AKA CYP2E1)
- Also metabolizes ethanol in the liver
- Inducible enzyme
- Higher Km for ethanol than alcohol dehydrogenase
- More significant at increased ethanol consumption
