ETHANOL

METABOLIS
M
by Marij Noor
 table of
CONTE
NT
IN tro d u c t io n R EQ U IR E D Ox id a tiv e
E NZ Y ME S p a th wa y s
E ne rg e t ic s To x ic e ffe c ts c o n tac t
 ETHAN
OL
• Ethanol, also known as ethyl alcohol or drinking alcohol, is a chemical
compound with the molecular formula C₂H₅OH.
• It is a clear, colorless liquid that is commonly used as a recreational drug and a
solvent in many industries.
• Ethanol has a long history of human use, primarily for its psychoactive effects
when consumed in alcoholic beverages.
 ETHANO
L
• After consumption ethanol is absorbed unaltered in the stomach
and small intestine.
• It distributes to all body tissues and fluid in direct proportion to
blood level.
• Less than 10% is excreted in urine, sweat and breath.

But after being metabolized it affects the entire body

Oxidative Pathway of Alcohol
Metabolism
 ENZYMES
REQUIRE
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• Microsomal ethanol oxidizing system(MEOS) enzymes as cytochrome
P450 and mixed function oxidase isoenzymes as CYP2E1
• Catalase(sometime)
 ALCOHOL
DEHYDROGENASE
• About 80 to 90% of the total hepatic ethanol uptake is processed via the alcohol
dehydrogenase system.

SYSTEM
• At first ethanol gets oxidized to acetaldehyde through cytosolic ADH with a reduction of NAD
to NADH
• Further on acetaldehyde is oxidized to acetate by the ALDH enzyme with the generation of
NADH.
• acetate is activated to acetyl coenzyme A in the liver BY synthetase enzyme
• then it can either enter the TCA cycle or the fatty acid synthesis pathway.
• However, most of the acetate that is generated enters the blood and is activated to acetyl-CoA
in skeletal muscles as they have high conc. Mitochondrial matrix synthetase enzyme (ACS-II)
Conti…
 MICROSOMAL ETHANOL
OXIDIZING SYSTEM
• At higher concentrations of ethanol, the microsomal ethanol oxidizing system (MEOS)
becomes activated.
• This pathway consists of a series of cytochrome P450 enzymes, for ethanol metabolism
and are located in the hepatic smooth endoplasmic reticulum (SER).
• Ethanol oxidation by MEOS does not affect the NADH/NAD+ ratio substantially,
therefore, it does not have the metabolic effects described for low concentrations of
ethanol.
• Although the MEOS system does not impact the NADH/NAD+ ratio, that is not to
suggest that induction of this system is without metabolic consequences. Induction of the
P450 system can negatively impact the metabolism of other drugs causing serious side
effects.
 MICROSOMAL ETHANOL
OXIDIZING SYSTEM
• In the MEOS pathway, CYP2E1 oxidizes ethanol to
acetaldehyde.
• This oxidation process requires the presence of
nicotinamide (NADPH) and molecular oxygen (O2).
• The reaction involves the transfer of electrons from
ethanol to oxygen, forming water, and generating
reactive oxygen species (ROS) as byproducts.
 ATP generated during alcohol metabolism varies as the route of
alcohol metabolism

Through cytosolic ADH and Through CYP2E1 of

mitochondrial ALDH Endoplasmic reticulum

• 1 cytosolic NADH+ 1 mt NADH=5ATP • 1st step oxidation from alcohol to

• Activation of acetate to acetyl-coenzyme A aldehyde consumes I NADPH the
requires 2 ATP form of 2.5 ATP.
• Oxidation of Acetyl –coA in TCA cycle • Activation of acetate to acetyl –coenzyme A
and ETC =10 ATP requires 2 ATP.
• However net ATP gained is 13 • Oxidation of acetate in the TCA generates 10
ATP
• So net generated 8 ATP
TOXIC EFFECTS OF
ALCOHOL
METABOLISM
 CHANGES IN FATTY ACiD
METABOLISM
• Overall high NADH and NAD+ ratio inhibits fatty acid oxidation thus they get
accumulated in the liver.
• NAD+ is required for fatty acid oxidation in the liver. Its deficiency is the main
cause of fat accumulation in the liver of alcoholics.

 KETO ACIDOSIS:
• High NADH/NAD+shifts the OAA in the TCA cycle towards malate synthesis so less OAA to
synthesize citrate.
• thereby acetyl –coA enters the ketone body synthesis pathway instead of the TCA cycle.
• So production of ketone bodies in the body remains in high conc but use is prevented in tissue
by acetate.
• Therefore the ketoacidosis condition arises.
 TOXICITY OF ACETALDEHYDE
TO THE BODY:
• As we all know acetaldehyde is toxic to the body.
• if the acetaldehyde converts acetate so no accumulation no toxicity.
• but if the intake of alcohol is more the acetaldehyde takes time to get oxidized and gets
accumulated producing the toxic effect.
• Aldehyde is highly reactive and binds covalently to amino groups, sulfhydryl groups,
nucleotides, and phospholipids to form “adducts.”

 Endotoxin release:
• Alcohol may cause the release of endotoxin (lipopolysaccharide), a product of gram-negative
bacteria, from the intestinal flora.
• Endotoxin stimulates the release of tumor necrosis factor (TNF) and other cytokines from
circulating macrophages and from Kupffer cells in the liver, causing cell injury.
 Alcohol and the Liver
• Fatty change:
present in over 90% of binge and chronic drinkers
liver is enlarged but patient is asymptomatic
changes are reversible with cessation of drinking
macrosteatosis w/o inflammation or necrosis
• Alcohol hepatitis:
only between 10 - 15% of alcoholics will develop alcoholic hepatitis
may have systemic symptoms and jaundice
hepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis)
thought to be a precursor of cirrhosis
probably more than HALF will go onto cirrhosis if ETOH is not stopped
• Alcoholic cirrhosis:
shrunken nodular liver with uniform small nodules (micronodular cirrhosis)
 References and
resources
 Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer
Health/Lippincott Williams & Wilkins, 2017, Chapter 12: Metabolism of Monosaccharides and Disaccharides,
Chapter 23: Effects of Insulin and Glucagon: Section IV.
 Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia:
Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 22: Generation of ATP from Glucose,
Fructose and Galactose, Chapter 33: Ethanol Metabolism.
Thank you

Questions?