METABOLISM OF ETHANOL

Objectives

By the end of this lecture you must be in position to

Know:
the major reactions involved in ethanol metabolism
alcohol-induced lactic acidosis,
 microsomal ethanol oxidizing system,
vitamin deficiencies,
effect on liver lipid metabolism
Alcohol / Ethanol /
Booze
Absorption

 Rapidly absorbed
 Absorbed in the duodenum and jejunum
 Readily dispersed throughout the body
The Phamacokinetics of Alcohol –
Metabolism and Excrection
 95% of all alcohol is digested
(metabolized) by an enzyme called
alcohol dehydrogenase
 80% via the liver
 15% via the stomach – a full stomach
can metabolize more
 Alcohol is exposed to first-pass
metabolism
 5% is excreted via the lungs
Metabolism of Alcohol by Men
and Women
 Alcohol is both fat and water –soluble
(why?)
 Since men have naturally less fat then
women and bigger blood vessels, men
have a lower Blood Alcohol Concentration
(BAC) than women
 Also, women have 50% less enzyme than
men, thus the metabolism rate is slower
 Remember – Alcohol metabolism is zero
order
 Dangers of Alcohol
Alcohol dehydrogenase provides a line of defense against a common
toxin in our environment.
•But alcohol dehydrogenase also modifies other alcohols, sometimes
producing even more dangerous products:
•Methanol, which is commonly used to “denature” ethanol rendering it
undrinkable, is converted to formaldehyde by alcohol dehydrogenase.
•The formaldehyde then causes severe damage, attacking proteins and
embalming them.
• Small amounts of methanol cause blindness, as the sensitive proteins in
the retina are attacked, and larger amounts, perhaps a glassful, lead to
widespread damage and death.
Sources of Alcohol
 Types of Alcohol
 Ethyl alcohol (ethanol)
 Methyl alcohol (methanol)
 Isopropyl alcohol (rubbing alcohol)
 Fermentation of fruits or grains by yeasts
 Beer and wine products
 10-15 % maximum ethanol content
 Distillation, heating and condensation process
 Liquors and liqueurs
 Structure (Form) & Function

•Our bodies create at least nine different forms of alcohol

dehydrogenase, each with slightly different properties.
• Most of these are found primarily in the liver, including the 3 form
• The  form is found in the lining of the stomach.
• Each enzyme is composed of two subunits.
•Ethanol is not the only target or substrate of these enzymes, they also
make important modifications to retinol, steroids, and fatty acids.
 Structure (Form) & Function
•Human alcohol dehydrogenases use two “helpers” to perform their
reaction on ethanol.
•The first are zinc ions (Zn++), which are used to hold and position the
alcohol group on ethanol.
•The second is the NAD cofactor (constructed using the vitamin niacin),
which actually performs the chemical reaction.
• The zinc atom, shown in light blue, is cradled by three amino acids
from the protein: cysteine 46 to the left, cysteine 174 to the right, and
histidine 67 above. The ethanol, shown in green and magenta, binds to
the zinc and is positioned next to the NAD cofactor, which extends
below the ethanol molecule in this illustration.
 Making Alcohol

•The enzyme alcohol dehydrogenase plays a central role in the most

ancient form of biotechnology: alcoholic fermentation.
•Yeast and many bacteria produce alcohol dehydrogenases. These
microbial enzymes catalyze the last step in the conversion of food into
metabolic energy, creating ethanol.
•Sugars are broken down and used for energy, forming ethanol as the
waste product, which is excreted into the liquid surrounding the cell.
•We have harnessed this process to produce alcoholic beverages: yeast is
allowed to ferment grain sugars to form beer, and yeast is allowed to
ferment grape juice to form wine.
 Making Alcohol
• Alcohol dehydrogenases in microbes function as tetramers.
• They are zinc-containing enzymes that utilize glucose.
•Each glucose molecule is broken down in a 10-step process called
glycolysis. The product of glycolysis is two three-carbon sugars, called
pyruvates, and ATP (adenosine triphosphate).
• The two pyruvates are then converted into ethanol and carbon dioxide.

The overall process of fermentation is to convert glucose sugar to alcohol and carbon dioxide gas:

C6H12O6        2 CH3CH2OH      +         2 CO2 

  sugar     alcohol             carbon dioxide gas
(glucose)    (ethyl alcohol or ethanol)
Making Alcohol
Making Alcohol
 Breaking Down Alcohol

• Alcohol dehydrogenase is our primary defense against alcohol, a

toxic molecule that compromises the function of our nervous system.
•The high levels of alcohol dehydrogenase in our liver and stomach
detoxify about one drink each hour.
•The alcohol is converted to acetaldehyde, an even more toxic
molecule and the main cause of hangovers!
• Acetaldehyde in turn is converted to acetate and other molecules
that are easily processed by our cells.
Human ADH
• Homodimer (two molecules)
• 2 x 373 amino acid residues
• 6 zinc ions (Zn++)
• 2 NAD cofactors
Human ADH Microbial
 Breaking Down Alcohol
Alcohol dehydrogenase

CH3CH2OH    + 2 NAD    CH3CHO    + 2 NADH

alcohol          cofactor  aldehyde cofactor
(ethanol) (acetaldehyde)

Acetaldehyde dehydrogenase 2

CH3CHO + H2O    CH3COOH

  aldehyde acid
(acetaldehyde) (acetic acid or
vinegar)
 Breaking Down Alcohol
Acetaldehyde dehydrogenase 2

CH3CHO + H2O    CH3COOH

  aldehyde acid
(acetaldehyde) (acetic acid or
vinegar)

The acetic acid can be used to form fatty acids (watch that
waistline!), or it can be further broken down into CO2 and water.
Small Amounts
Unmetabolized (10%)
 Sweat
 Urine
 Breath
 Small Amounts
Unmetabolized (10%)
 Sweat
 Urine
 Breath
 1st Pass Metabolism

 Occurs in the Stomach

 Gender Differences Exist: Men
have a > level of ADH than
women
 Early metabolism translates to
lower BAC levels
 2nd Pass Metabolism

 Occurs in the Liver

 1st liver enzyme--Alcohol
Dehydrogenase (ADH)----->
Acetaldehyde
 2nd liver enzyme--Acetaldehyde
Dehydrogenase----> Acetic Acid
 Acetic Acid oxidized by body
organs----> CO2 + H2O
 Blood Alcohol
Concentration
 THE RATIO OF ALCOHOL IN THE
BLOOD TO THE TOTAL VOLUME
OF BLOOD EXPRESSED AS A
PERCENT
 THE PERSUMPTIVE LEVEL OF
INTOXICATION = .10%
 FOR A 160 LB. INDIVIDUAL EACH
DRINK = .02% *note size
 PROBLEM

 If an individual weighing 160

lbs. consumes 2 drinks per hour,
what will his/her BAC level be at
the end of that time?
Microsomal ethanol oxidizing system (MEOS)

 Moderate-excessive intakes
 Microsomal ethanol oxidizing system (MEOS)
Requires energy to operate
Potential for drug toxicitites
 Catalase pathway
Minor contribution
Metabolism
Alcohol Main Location of Alcohol Intake Extent of
Metabolic Pathway Activity Level That Participation in
Pathway Activates Alcohol
Pathway Metabolism

ADH pathway Stomach Low to moderate Major role

Liver (mostly) intake (metabolizes
about 90% of
alcohol)
MEOS Liver Moderate to Role increases in
excessive intake importance with
increasing
alcohol intake
levels

Catalase pathway Liver Moderate to Minor

Other cells excessive intake
Ethanol-Induced Metabolic
Acidosis

Ethanol Acetaldehyde

NAD+ NADH + H+

L-Lactate Pyruvate
L-Lactic Acidosis
Overproduction of L-lactic Acid
 Net production of L-lactic acid occurs when the body
must regenerate ATP without oxygen
 1 H+ is produced per ATP regenerated from glucose
 Because a patient will need to regenerate 72 mmol of
ATP per minutes, As much as 72 mmol/min of H+ can be
produced in case of anoxia
 2ATP2 ADP + 2 Pi + biological work
 Glucose + 2 ADP + 2 Pi  2 H+ + 2L-Lactate- + 2 ATP
 Rapid increase in metabolic rate: strenuous exercise
 Increase Glycolysis
 Normal Lactate/Pyruvate ratio suggest that the cause is
not related to anaerobic metabolism or anoxia

L-Lactic Acidosis
Underutilization of L-lactic Acid

 Decreasedgluconeogesis: liver
problems, inhibitors by drugs
 Decreased Transamination:
malnutrition
 Decreased oxidation: anaerobic
conditions, PDH(in full) problems
 Lactic Acidosis
Type A
• Severe hypoxemia
• Acute circulatory shock
(poor delivery of O2)
• Severe anemia (low
capacity of blood to
carry O2)
• Prolonged seizures
• Exhausting exercise
Type B
PDH problems: thiamin deficiency
or an inborn error
Decreased gluconeogenesis, liver
failure, biguanide, alcohol
Excessive formation of lactic acid:
malignant cells, low ATP, inhibition
of mitochondrial generation of ATP:
cyanide, uncoupling oxidation and
phosphorylation, alcohol
intoxication
Health Effects
 Alcohol is highly caloric but has little nutritional
value
 Vitamin and trace element deficiencies are linked to
alcohol
 Liver and stomach cancers
 Metabolic Tolerance – Increase of alcohol digesting
enzyme by the liver
 Liver damage – 75% of all deaths due to alcoholism
are caused by cirrhosis of the liver, the 7th most
common cause of death in the US
ALCOHOL’S EFFECT ON THE BODY
DIGESTIVE SYSTEM:
 IRRITANT
 INCREASING AMOUNTS IMPEDE OR STOP DIGESTION
 PYLORIC VALVE MAY BE EFFECTED “STUCK”
ALCOHOL’S EFFECT ON THE BODY
CIRCULATORY SYSTEM
 MINOR EFFECTS
 HEARTBEAT & BLOOD PRESSURE LITTLE EFFECT
 VASODILATOR OF SURFACE VESSELS
 BODY HEAT LOSS (HYPOTHERMIA)
ALCOHOL’S EFFECT ON THE BODY
KIDNEYS
 INCREASED URINE OUTPUT
 CONSUMING LARGE QUANTITIES OF LIQUID
 REDUCES THE PITUITARY HORMONE ADH (ANTIDIRURETIC HORMONE)
ALCOHOL’S EFFECT ON THE BODY
LIVER
 ELIMINATES LIVER PRODUCTION OF GLUCOSE CREATING
HYPOGLYCEMIA
 BRAIN DEPRIVED OF PROPER NOURISHMENT
 WEAKNESS, NERVOUSNESS, SWEATY, HEADACHE, TREMORS
 FATTY LIVER
ALCOHOL’S EFFECT ON THE BODY
WHITE BLOOD CELLS
 ACUTE ALCOHOL CONSUMPTION SUCH AS BINGE DRINKING HAS A
DIRECT EFFECT ON:
 WBC RESERVES
 CHEMOTAXIS
 WBC ADHERENCE TO BACTERIA
ALCOHOL’S EFFECT ON THE BODY
CENTRAL NERVOUS SYSTEM
1 dk/hr BAC .02 little change
2 dk/hr BAC .05 drinker high, judgement center of brain affected,
inhibitions lowered
3 dk/hr BAC .10 judgement is nil, muscle coordination depressed,
stagger, slur speech
Read about

 D-lactic acidosis and compare with L-lactic acidosis

 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)
Fatty Change Biochemistry

 Catabolism of fat by peripheral tissues is

increased, and there is increased delivery of free
fatty acids to the liver
 An excess of NADH over NAD stimulates lipid
biosynthesis
 Oxidation of fatty acids by mitochondria is
decreased
 Acetaldehyde forms adducts with tubulin and
impairs function of microtubules, resulting in
decreased transport of lipoproteins from the liver
Biochemical

Abnormal Labs:

Transferrin: 155 (low)

Glucose: 130 (high)
Bilirubin: 1.5 (high)
AST: 50 (high)
LDH: 323 (normal)
Alk Phospate 178 (high)
CPK: 245 (high)
Cholesterol: 225 (high)
HDL: 40 (low)
Triglycerides: 250 (high)
WBC: 14.5x 103/mm3 (high)
HCT: 35.7g/dl (low)
MCV: 101.5 um3 (high)
Clinical

 Thin
 Temporal muscle wasting
 Appears to be in discomfort
 No edema
 Bowl sounds normal
 Tenderness in epigastric religion
 Liver and spleen not enlarged
  Ethanol and vitamin deficiencies

 Vitamin and trace element deficiencies are linked to

alcohol
 Vitamin B1

 Thiamine, also known as vitamin B1, is fairly

ubiquitous.
 Thiamine deficiency is uncommon except in
alcoholics as a result of nutritional deficiencies and
malabsorption.
 The classic clinical triad of dementia, ataxia
(difficulty with walking), and eye findings may be
seen, but more commonly, only forgetfulness is
noted
Vitamin B1
 Sometimes, thiamine deficiency can lead to
vague symptoms such as leg numbness or
tingling.

 Because thiamine is water soluble, it can be
added to intravenous fluids and administered in
that way.

 Other manifestations include beri beri, which is

cardiac involvement leading to a high cardiac
output, and vasodilation.

 Affected patients often feel warm and flushed,

and they can have heart failure.
Vitamin B1

 Vitamin B1
 Thiamine
 Involved in carbohydrate metabolism
 Helps body metabolize glucose, affects central
nervous system
 Deficiency causes Beri beri
(Singlese, “I can’t, I can’t”)
 Home work
 List the enzymes involved in ethanol metabolism
 Write down the major reactions involved in ethanol
metabolism
 Briefly describe the microsomal ethanol oxidizing system
 Outline some of the vitamin deficiencies related to ethanol
metabolism.

THANKS FOR ATTENDING