Alcohol Metabolism

Ethanol's Entry & ADH Action - Booze Breakdown Begins

• Ethanol Entry & Distribution:

  • Rapid absorption: Stomach (~20%), Small Intestine (~80%).
  • Distributes in total body water; readily crosses Blood-Brain Barrier (BBB) & placenta.

• ADH Pathway: The Primary Breakdown Route:

  • Location: Cytosol of hepatocytes. (📌 'C' for Cytosol, 'C' for $C_2H_5OH$)
  • Enzyme: Alcohol Dehydrogenase (ADH).
  • Reaction: $CH_3CH_2OH + NAD^+ \xrightarrow{ADH} CH_3CHO + NADH + H^+$
  • Product: Acetaldehyde ($CH_3CHO$) - highly reactive & toxic.
  • Cofactor Dynamics: $NAD^+$ consumed, $NADH$ produced $\rightarrow$ ↑ $NADH/NAD^+$ ratio (key metabolic impact).
  • Kinetics: Zero-order above ~10 mg/dL (or ~2 mM) ethanol.
    • Metabolizes a constant amount: approx. 7-10 g/hour.

⭐ Alcohol metabolism predominantly follows zero-order kinetics at pharmacologically relevant concentrations, meaning a constant amount is processed per unit time, irrespective of blood alcohol levels above a certain threshold.

Acetaldehyde's End & MEOS Role - Toxic Takedown Time

Acetaldehyde Fate (ALDH Pathway)

• Oxidized to Acetate by Aldehyde Dehydrogenase (ALDH), mainly ALDH2.
• Location: Mitochondria (📌 'M'ighty 'M'itochondria 'M'op up Acetaldehyde).
• Reaction: $CH_3CHO + NAD^+ + H_2O \xrightarrow{ALDH} CH_3COOH + NADH + H^+$
• Product: Acetate (→ Acetyl-CoA → TCA cycle).
• ALDH2 Deficiency: Flushing, nausea (common in East Asians, due to acetaldehyde buildup).

Microsomal Ethanol Oxidizing System (MEOS)

• Alternative pathway; active at high ethanol concentrations.
• Location: Smooth Endoplasmic Reticulum (SER) of liver cells.
• Key Enzyme: CYP2E1 (a Cytochrome P450 isoform).
• Reaction: $CH_3CH_2OH + NADPH + H^+ + O_2 \xrightarrow{CYP2E1} CH_3CHO + NADP^+ + 2H_2O$
• Chronic alcohol use induces CYP2E1:
  • Contributes ~10-20% to overall ethanol metabolism.
  • Results in:
    • ↑ Alcohol tolerance.
    • ↑ Acetaldehyde & Reactive Oxygen Species (ROS) → hepatotoxicity.
    • Altered drug metabolism (e.g., paracetamol, leading to ↑ toxicity).

⭐ Chronic alcohol consumption induces the MEOS pathway, particularly CYP2E1, leading to increased alcohol tolerance and altered drug metabolism.

Metabolic Mayhem & Clinical Links - Clinical Chaos Chronicles

Chronic alcohol intake elevates NADH/NAD+ ratio, leading to widespread metabolic disruption. Acetaldehyde accumulation also causes significant toxicity.

Key Metabolic Derangements (due to ↑NADH/NAD+):

• 📌 Mnemonic for overall ↑NADH/NAD+ effects: 'LACTate HIKEs' (Lactic Acidosis, Hypoglycemia, Acetyl-CoA to Ketones/Fatty acids, Hyperuricemia, steatosis).

Acetaldehyde Toxicity:

• Acute: Flushing, nausea, headache (ALDH2 deficiency worsens).
• Chronic: Liver damage (fibrosis, cirrhosis), carcinogen.

Other Major Clinical Links:

• Wernicke-Korsakoff syndrome (Thiamine deficiency).
• Alcoholic Ketoacidosis (AKA).
• Fetal Alcohol Syndrome (FAS).
• Methanol/Ethylene Glycol Poisoning:
  • Methanol $\rightarrow$ Formic acid (blindness).
  • Ethylene Glycol $\rightarrow$ Oxalic acid (renal failure).
  • Antidotes: Fomepizole, Ethanol.
• Disulfiram: Inhibits ALDH $\rightarrow$ acetaldehyde buildup (aversive).

⭐ Fomepizole is a competitive inhibitor of alcohol dehydrogenase and is the preferred antidote for methanol and ethylene glycol poisoning.

High‑Yield Points - ⚡ Biggest Takeaways

• Ethanol primarily metabolized by cytosolic ADH then mitochondrial ALDH.
• ADH is the rate-limiting enzyme in this pathway.
• MEOS (CYP2E1) is an inducible system, important at high alcohol concentrations.
• Acetaldehyde is toxic, causing flushing, nausea, and organ damage.
• Disulfiram inhibits ALDH, leading to acetaldehyde accumulation and severe symptoms.
• ↑ NADH/NAD+ ratio from alcohol metabolism causes lactic acidosis, hypoglycemia, fatty liver.
• Fomepizole (ADH inhibitor) or ethanol treats methanol/ethylene glycol poisoning.