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L 38 Alcohol Metabolism (Lecture 38) Notes

Part 1. Alcohol Absorption and Distribution

  • A) Generalities
    • Alcohols: family of molecules with hydroxyl (-OH) groups bound to carbon skeletons; ethanol (ethyl alcohol) is the alcohol in beverages and is used interchangeably with “alcohol” in this lecture.
    • Alcoholic beverages are the main dietary source of ethanol, but traces of ethanol and other alcohols are present in foods (banana, bread, fruit juice, eggs, etc.), making alcohol metabolism a basal function of the human body.
    • Ethanol production basis: ethanol fermentation from carbohydrates by microorganisms (e.g., Saccharomyces cerevisiae).
    • A standard drink contains roughly 14 g of pure alcohol (examples: 12 oz beer at 5%, 5 oz wine at 12%, 1.5 oz distilled spirits at 40%).
    • N.B.: The lecture emphasizes metabolic effects of alcohol, not CNS effects.
  • B) (Production &) Absorption of Ethanol
    • Endogenous production: the GI tract can produce ethanol in mammals via gut microbiome fermentation; observed in normally fed rats with low caecal ethanol (~0.9 mM).
    • Auto-brewery syndrome: in humans, gut microbiome imbalances plus carb-rich diet can produce ethanol to intoxication levels; diagnosed via blood or breath ethanol after a glucose challenge.
    • Absorption characteristics: ethanol is small, fully miscible in water, diffuses through lipid membranes without active/passive transport, rapidly absorbed.
    • Absorption sites and rate: primary absorption in small intestine (highly vascularized); slower in stomach due to lower vasculature. Factors modulating absorption:
    • Food in stomach slows absorption.
    • Beverage ethanol concentration: higher content speeds absorption, but spirits (40%) delay gastric emptying, inhibiting absorption.
    • Carbonation increases absorption.
    • Sex differences: for the same amount consumed, women tend to have higher blood alcohol concentrations due to smaller body size, higher fat proportion (less total body water for diffusion), and lower gastric ADH activity.
    • Visual note: Blood alcohol curves differ by beverage type and sex (described in lecture visuals).
  • C) Distribution of alcohol in the body
    • Ethanol distributes in the body water; most tissues (heart, brain, muscle) experience similar alcohol concentrations as blood.
    • Distribution is faster in organs with rich blood supply; liver exposure is high because blood comes via portal vein from stomach/intestine.
    • Bone and adipose tissue are relatively less exposed to ethanol.
    • In pregnancy, ethanol crosses the placenta, posing risks for miscarriage, preterm birth, and fetal alcohol spectrum disorders (FASD).

Part 2. Metabolism of Alcohol: Oxidation

  • A) Alcohol Dehydrogenases (ADHs)
    • Enzymes: ADHs oxidize ethanol to acetaldehyde, with concomitant reduction of NAD+ to NADH:
    • Reaction: \mathrm{CH3CH2OH + NAD^+ \rightarrow CH_3CHO + NADH + H^+}
    • Localization and diversity: ADHs are abundant in the cytosol of liver cells and stomach; humans express many ADH variants encoded by multiple genes (7 genes, 11 isoforms), with tissue- and rate-specific expression.
    • Methanol poisoning: ADHs also oxidize methanol to formaldehyde; formaldehyde is a precursor to formic acid, a toxic metabolite. Methanol poisoning often from tainted alcohol; treatment historically used ethanol to outcompete methanol for ADH; modern treatments include Fomepizole (an ADH inhibitor).
  • B) Oxidation in the stomach – First pass effect
    • The stomach also contains ADHs that oxidize ethanol to acetaldehyde before absorption, reducing ethanol bioavailability (first-pass effect).
    • The first-pass effect is a protective barrier; it is stronger in men than in women.
    • Chronic/excessive alcohol use can cause gastritis, reducing ADH activity and diminishing the first-pass effect.
  • C) Oxidation in the liver
    • The liver is the main organ for ethanol oxidation and uses two pathways:
    • 1) Liver ADHs (cytosolic): oxidize ethanol to acetaldehyde, generating NADH in the process; high ADH activity contributes to intracellular NADH buildup.
    • 2) Microsomal Ethanol Oxidizing System (MEOS): ER-associated cytochrome P450 enzymes, notably CYP2E1, oxidize ethanol to acetaldehyde with concomitant NADPH oxidation to NADP+ and water:
    • Reaction: \mathrm{CH3CH2OH + NADPH + O2 \rightarrow CH3CHO + NADP^+ + H_2O}
    • Km values and activity: ADH has a higher affinity for ethanol (Km ≈ 1–10 mg%), while CYP2E1 has lower affinity (Km ≈ 50–80 mg%), so MEOS contributes more at higher blood alcohol levels.
    • Chronic alcohol increases CYP2E1 expression, increasing metabolic tolerance and contributing to drug interactions (MEOS metabolizes many substrates beyond ethanol).
    • 3) Acetaldehyde Dehydrogenases (ALDH): mitochondrial enzymes that oxidize acetaldehyde to acetic acid, generating NADH:
    • Reaction: \mathrm{CH3CHO + NAD^+ \rightarrow CH3COOH + NADH}
    • Acetaldehyde toxicity and ALDH deficiency:
    • Alcohol flush reaction results from ALDH deficiency; common in East/Southeast Asian populations (30–50% in Chinese, Japanese, Koreans).
    • Disulfiram (Antabuse®) inhibits ALDH, causing acetaldehyde accumulation after alcohol intake and unpleasant reactions (used to deter drinking).
  • D) Alcohol Flush Reaction
    • Mechanism: accumulation of acetaldehyde due to low ALDH activity leads to facial flushing, nausea, headaches, and general malaise.
    • Epidemiology: high prevalence in certain populations; reflects genetic variation in ALDH2 enzyme.
  • E) Disulfiram
    • Pharmacology: ALDH inhibitor used to treat Alcohol Use Disorder; inhibition causes acetaldehyde buildup after drinking, producing aversive effects that reduce intake.

Part 3. Alcohol and human health

  • A) Serum markers of alcohol-induced liver damage
    • Elevated GGT (gamma-glutamyltransferase): reflects oxidative stress and bile duct injury; increased leakage into blood.
    • Elevation of AST and ALT with a ratio about 2:1 in alcohol-related damage (vs ~1:1 in non-alcoholic liver disease).
    • ALT is cytosolic; AST is mitochondrial; normal ratio suggests mitochondria involvement in damage.
    • Vitamin B6 (pyridoxine) deficiency is common in Alcohol Use Disorder and disproportionately affects ALT activity relative to AST, contributing to the 2:1 or higher AST/ALT ratio in alcohol-related damage.
    • In hepatocytes, the baseline AST/ALT ratio is about 2.5:1.
  • B) Direct Toxicity of Alcohol
    • Ethanol disrupts plasma membranes and induces oxidative stress, causing cellular damage.
    • Very high BAC (≈0.4%+) can be fatal in alcohol-naïve individuals; those with Alcohol Use Disorder may tolerate higher BAC.
  • C) Effects of Acetaldehyde production
    • Acetaldehyde has relatively low affinity for an antioxidant response and is poorly upregulated in individuals with alcohol use disorder.
    • Accumulation of acetaldehyde is toxic: reacts with cellular constituents and generates reactive oxygen species (ROS), contributing to cancer risk.
  • D) Effects of NADH production
    • Ethanol oxidation dramatically increases hepatic NADH; elevated NADH/NAD+ redox ratio drives:
    • Increased lactate production via lactate dehydrogenase, promoting lactic acidosis under hypoxic or dehydrated conditions.
    • Inhibition of beta-oxidation of fatty acids, leading to hepatic steatosis and potential progression to fibrosis, cirrhosis, or cancer.
    • Inhibition of the TCA cycle and overload of electron transport chain, contributing to ATP depletion and cell injury.
  • E) MEOS and ethanol-drugs interactions
    • Chronic exposure induces MEOS enzymes (notably CYP2E1), heightening metabolism of other drugs and xenobiotics; some metabolites are more toxic than parent compounds.
    • Consequences include increased vulnerability to environmental toxins and interactions with prescription/OTC meds and illicit drugs (e.g., acetaminophen, pentobarbital, cocaine).
    • Example: alcohol-acetaminophen interaction; acetaminophen metabolism shifts toward CYP2E1-derived NAPQI, a hepatotoxin, in Alcohol Use Disorder due to elevated CYP2E1.
  • F) Alcohol-Induced Vitamin deficiencies
    • Nutritional status affected because ethanol provides energy but reduces intake of other nutrients; GI and pancreatic damage impairs digestion/absorption; liver dysfunction impairs storage and metabolism of nutrients.
    • Common deficiencies in Alcohol Use Disorder:
    • Thiamine (Vitamin B1): critical in energy metabolism; deficiency linked to Wernicke-Korsakoff syndrome (ataxia, ophthalmoplegia, confusion).
    • Folate (Vitamin B9): essential for RBC formation; deficiency leads to anemia and hematologic changes.
    • Pyridoxine (Vitamin B6): cofactor for transaminases; deficiency perturbs protein metabolism and can cause inflammation and anemia.
    • Chronic alcohol dependence-related malnutrition aggravates alcohol’s direct hepatic effects, contributing to cirrhosis risk.

MECHANISTIC SUMMARY: Alcohol oxidation in stomach and liver

  • First-pass metabolism (stomach ADHs): reduces systemic ethanol exposure; stronger in men; diminished with gastritis.
  • Hepatic metabolism: ADHs (cytosolic) produce acetaldehyde and NADH; MEOS (CYP2E1) contributes at higher ethanol levels and broadens substrate scope, including drug interactions; ALDHs convert acetaldehyde to acetate with additional NADH, feeding into acetyl-CoA production.
  • Consequences of NADH accumulation: redox imbalance; shifts in metabolism (lactate, lipids); energy deficit.
  • Consequences of acetaldehyde accumulation: direct toxicity, ROS generation, cancer risk, and tissue injury; ALDH deficiency leads to flushing and discomfort.

Study questions (with answers)

  • 1) Which of the following products are derived from alcohol oxidation in the liver?
    • A. acetaldehyde
    • B. NADH
    • C. NADP+
    • D. All of the above
    • Answer: D
  • 2) Stomach oxidation of alcohol is decreased
    • A. in individuals with alcohol use disorder
    • B. in women when compared to men
    • C. by gastritis
    • D. All of the above
    • Answer: D
  • 3) Alcohol oxidation by hepatic ADHs results in a
    • A. decrease in lactic acid production
    • B. increase in NAD+ concentration
    • C. decrease in pyruvate
    • D. decrease in triglyceride accumulation
    • Answer: C
  • 4) Microsomal ethanol oxidizing system (MEOS)
    • A. oxidizes alcohol in the stomach
    • B. is increased with increased consumption of alcohol
    • C. is very active in women
    • D. generates a large amount of energy during alcohol oxidation
    • Answer: B
  • 5) Wernicke-Kosarkoff syndrome seen in alcohol use disorder is a result of a deficiency in
    • A. vitamin B12
    • B. vitamin B6
    • C. vitamin A
    • D. Thiamin
    • Answer: D

Key terms and concepts

  • Absorption and distribution: ethanol, auto-brewery syndrome, rapid absorption, slow elimination, stomach vs small intestine factors, placental transfer.
  • Alcohol oxidation: ADHs, methanol poisoning, gastric ADH (first pass), hepatic ADHs and ALDHs, acetaldehyde, NADH, MEOS, CYP2E1.
  • Health implications: serum markers (GGT, AST/ALT with ~2:1 ratio in alcohol damage), acetaldehyde toxicity, NADH/NAD+ redox effects, lactic acidosis, steatosis, ATP depletion, cirrhosis, drug interactions.
  • Vitamin deficiencies associated with alcohol: thiamine (B1), folate (B9), pyridoxine (B6).
  • Alcohol and health guidelines: moderate drinking defined as up to 2 drinks/day for men, 1 drink/day for women (DGAs).
  • Enzyme inhibitors and drug interactions: Fomepizole (ADH inhibitor for methanol poisoning); Disulfiram (ALDH inhibitor for AUD).
  • NADH/NAD+ imbalance consequences: lactate production, TCA inhibition, fatty acid oxidation suppression, ATP depletion.
  • MEOS induction and drug interactions: CYP2E1 upregulation increases metabolism of xenobiotics and potential for toxic metabolites like NAPQI from acetaminophen in co-exposure.
  • Fetal risk: fetal alcohol spectrum disorders (FASD) due to placental transfer and developmental impact.
  • Notable numeric references: standard drink ~14 g alcohol; KmADH ≈ 1–10 mg%; KmCYP2E1 ≈ 50–80 mg%.

Connections to broader concepts

  • Metabolism shifts under redox stress: NADH production alters glycolysis, gluconeogenesis, and fatty acid oxidation, linking to metabolic diseases such as fatty liver and lactic acidosis.
  • Drug metabolism and toxicology: MEOS (CYP2E1) is a common pathway for xenobiotics; induction by chronic alcohol use alters pharmacokinetics and toxicity of many drugs.
  • Nutritional biochemistry: alcohol-related malabsorption, malnutrition, and micronutrient deficiencies interact with liver function, immune function, and neurological health.
  • Public health and clinical implications: prevalence of AUD, markers of liver injury, and genetic predispositions (ALDH2 deficiency) influence risk assessment and treatment strategies.

Equations and reactions (LaTeX)

  • Alcohol dehydrogenase reaction:
    \mathrm{CH3CH2OH + NAD^+ \rightarrow CH_3CHO + NADH + H^+}
  • MEOS (CYP2E1) reaction:
    \mathrm{CH3CH2OH + NADPH + O2 \rightarrow CH3CHO + NADP^+ + H_2O}
  • Acetaldehyde oxidation to acetate (ALDH):
    \mathrm{CH3CHO + NAD^+ \rightarrow CH3COOH + NADH}
  • Acetate to acetyl-CoA (via Acetyl-CoA synthetase):
    \mathrm{CH3COO^- + CoA + ATP \rightarrow \mathrm{CH3CO ext{-}SCoA} + AMP + PP_i}
  • Mechansim of acetaldehyde toxicity: acetaldehyde forms ROS and adds to cellular constituents, contributing to carcinogenic processes.