BIOC- Ethanol metabolism

Ethanol

a small, water-soluble molecule that is rapidly absorbed in the gastrointestinal tract and
transported to the liver for metabolism

Ethanol metabolism

primarily occurs in the liver through three key enzymatic pathways

• Alcohol dehydrogenase

• Acetaldehyde dehydrogenase

• microsomal ethanol oxidizing system

Alcohol Dehydrogenase (ADH)

is the primary enzyme responsible for the oxidation of ethanol to
acetaldehyde (located in the cytosol of hepatocytes) ~severval isoforms

Acetaldehyde Dehydrogenase (ALDH)

Converts toxic acetaldehyde into acetate, which is less harmful and can be
further metabolized. (located in mitochondria)

ALDH2 mutations

Certain populations have ___________ leading to reduced
activity, resulting in acetaldehyde accumulation and unpleasant effects such as flushing
and nausea.

Microsomal Ethanol Oxidizing System (MEOS)

An alternative pathway activated during chronic alcohol consumption (smooth ER)

Cytochrome P450 2E1 (CYP2E1)

plays a major role in ethanol metabolism
under high alcohol intake

reactive oxygen species (ROS), contributing to liver damage

Chronic ethanol consumption induces CYP2E1, increasing ethanol clearance
but also generating

ADH and ALDH

polymorphisms significantly impact ethanol metabolism

ALDH2*2 variant

that impairs acetaldehyde breakdown, leading to flushing syndrome

East Asian populations frequently have an ______

ADH activity and a higher peak blood alcohol
concentration than men

Women generally have lower

age due to reduced hepatic enzyme efficiency

Ethanol metabolism decreases with

Chronic Alcohol Consumption

Induces MEOS, leading to faster ethanol metabolism but increased oxidative
stress and toxicity

NADH, which enters oxidative phosphorylation,
leading to ATP generation

Ethanol oxidation produces

ADH Step

1 NADH (~2.5 ATP per ethanol molecule)

ALDH Step

1 NADH (~2.5 ATP per ethanol molecule)

Acetate Metabolism steps

Converted to acetyl-CoA, entering the TCA cycle
and generating ~10 ATP

ethanol molecule

Approximately 13 ATP per

MEOS Pathway (CYP2E1)

Uses NADPH instead of NAD+, resulting in a lower net
ATP yield. The net ATP yield from ethanol oxidation via CYP2E1 is approximately 8
ATP per ethanol molecule due to the consumption of NADPH, which does not directly
contribute to ATP synthesis

NADH/NAD+ ratio, disrupting various
metabolic pathways

Ethanol metabolism leads to a significant increase in th

hypoglycemia, especially in fasting individuals

Inhibition of Gluconeogenesis

Excess NADH inhibits key gluconeogenic enzymes, causing

Lactic Acidosis

Increased NADH drives pyruvate to lactate conversion, leading to metabolic acidosis

Inhibition of Fatty Acid Oxidation

High NADH levels prevent fatty acid oxidation, leading to triglyceride accumulation and
fatty liver disease

Hyperuricemia

Lactic acidosis reduces uric acid excretion, contributing to gout flare-ups

Ketoacidosis

Increased acetyl-CoA from ethanol metabolism favors ketone body synthesis, causing
alcoholic ketoacidosis

Acetaldehyde Toxicity

Acetaldehyde, a highly reactive and toxic intermediate, causes several harmful effects such as cellular and tissue damage, mitochondrial dysfunction, carcinogenic effects, and neurological effects

Cellular and Tissue Damage if Acetylaldehyde

Binds to proteins, lipids, and DNA, leading to oxidative stress and inflammation

Mitochondrial Dysfunction of acetaldehyde

Disrupts mitochondrial function, impairing ATP production and promoting cell death

Carcinogenic Effects

Acetaldehyde forms DNA adducts, increasing the risk of esophageal and liver cancer

Immune System Activation of acetyladehyde

Promotes cytokine release, contributing to alcohol-induced hepatitis

Neurological Effects

Acetaldehyde impairs neurotransmitter balance, contributing to hangover symptoms and
long-term cognitive deficits

alcohol dehydrogenase (ADH) and acetaldehyde
dehydrogenase (ALDH)

Major route of metabolism in the liver is through

ADH1 family

The ADH that exhibit the highest specificity for ethanol are members of the

nausea and vomiting

Accumulation of acetaldehyde causes

ALDH inhibitors

can be used for the treatment of alcoholism

MEOS

The other principal route of ethanol oxidation in the liver is the

CYP2E1

has a much higher Km for ethanol than the ADH1 family members

CYP2E1 levels

Chronic consumption of ethanol increases hepatic

individual to individual

The routes and rates of ethanol oxidation vary from

NADH/NAD+ ratio in the liver

Many of the acute effects of ethanol ingestion arise from the increased

oxidation of fatty acids

The high NADH/NAD+ ratio inhibits the

lactate, resulting in lactic acidosis

Balance in the lactate dehydrogenase reaction is shifted toward

ethanol consumption because ethanol consumption may
make their condition worse

Patients suffering from gout should avoid

hepatic protein synthesis

Acetaldehyde-adduct formation with amino acids decreases

H2O2 induced lipid
peroxidation

Acetaldehyde binds to glutathione and diminishes its ability to protect against