U01.01.078 Ethanol metabolism

Ethanol metabolism involves a series of biochemical reactions that occur primarily in the liver, with significant contributions from enzymes like alcohol dehydrogenase and acetaldehyde dehydrogenase. This process influences various metabolic pathways by altering the NADH/NAD+ ratio, which has wide-ranging effects on physiological states such as lactic acidosis, fasting hypoglycemia, and fatty liver (hepatic steatosis).

Key Enzymes and Components

Enzyme/Component	Function/Description
Alcohol dehydrogenase	Converts ethanol to acetaldehyde, primarily in the cytosol.
Acetaldehyde dehydrogenase	Converts acetaldehyde to acetate, primarily in the mitochondria.
Catalase	Converts ethanol to acetaldehyde in the peroxisomes (minor role).
CYP2E1	Microsomal enzyme that also metabolizes ethanol, contributing to ROS production.
Fomepizole	Inhibits alcohol dehydrogenase, used as an antidote for methanol or ethylene glycol poisoning.
Disulfiram	Inhibits acetaldehyde dehydrogenase, leading to acetaldehyde buildup and discouraging alcohol consumption.

Pathways Involved

Pathway	Effect of Ethanol Metabolism
TCA Cycle	Inhibited by high NADH/NAD+ ratio, leading to the diversion of acetyl-CoA into ketogenesis.
Gluconeogenesis	Inhibited by low NAD+, causing fasting hypoglycemia.
Glycolysis	Inhibited by high NADH/NAD+ ratio, contributing to lactic acidosis.
Lipogenesis	Stimulated by excess NADH, leading to hepatic steatosis (fatty liver).
Ketogenesis	Stimulated by excess NADH, leading to ketoacidosis.

NADH/NAD+ Ratio and Metabolic Effects

Elevated NADH/NAD+ ratio disrupts the normal function of several metabolic pathways in the liver, leading to:
- Lactic acidosis: Inhibition of pyruvate conversion to lactate due to reduced NAD+ availability.
- Fasting hypoglycemia: Decreased gluconeogenesis due to the diversion of oxaloacetate (OAA) to malate.
- Ketoacidosis: Increased diversion of acetyl-CoA into ketogenesis rather than the TCA cycle.
- Hepatic steatosis: Enhanced lipogenesis due to the increased availability of glycerol-3-P.

Key Points to Remember

NAD+ is the limiting reagent: Alcohol metabolism heavily depends on NAD+ for the oxidation of ethanol and acetaldehyde.
Zero-order kinetics of alcohol dehydrogenase: The rate of ethanol metabolism is constant and independent of ethanol concentration, leading to the possibility of ethanol overdose.
Pathway inhibition: Elevated NADH levels inhibit the TCA cycle and gluconeogenesis while promoting lipogenesis and ketogenesis.
Clinical relevance of Fomepizole and Disulfiram:
- Fomepizole is used as an antidote for methanol or ethylene glycol poisoning by inhibiting alcohol dehydrogenase.
- Disulfiram causes acetaldehyde accumulation by inhibiting acetaldehyde dehydrogenase, which results in hangover-like symptoms and discourages alcohol consumption.

Clinical Implications

Lactic acidosis:
- Caused by impaired conversion of pyruvate to lactate due to NADH buildup.
- Contributes to an anion gap metabolic acidosis.
Fasting hypoglycemia:
- Decreased gluconeogenesis due to the diversion of OAA to malate.
- Common in alcoholics who are fasting.
Ketoacidosis:
- Excess acetyl-CoA is diverted into ketogenesis rather than entering the TCA cycle, leading to ketoacidosis.
Hepatic Steatosis:
- Enhanced lipogenesis and triglyceride synthesis due to elevated NADH/NAD+ ratio.
- Characterized by fatty liver.

Learning Objectives

Understand the enzymes involved in ethanol metabolism, including their locations and functions.
Recognize how ethanol metabolism affects the NADH/NAD+ ratio and its subsequent impact on key metabolic pathways.
Identify the clinical significance of drugs like fomepizole and disulfiram in managing ethanol-related toxicity and alcohol use disorder.

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