Transcript Alcohol Metabolism

Alcohol Metabolism
Break Down and Removal
Mohamad Nusier MD. PhD.
Introduction
In the United States, approximately 100 000 deaths are
attributed to alcohol abuse each year. In 2009, the World
Health Organization listed alcohol use as one of the
leading causes of the global burden of disease and
injury. Alcoholic liver disease, a direct result of chronic
alcohol abuse, insidiously destroys the normal functions of
the liver. The end result of the disease, cirrhosis, ends in a
dysfunctional and diffusely scarred liver.
Alcohol Metabolism and the Liver
The liver is the principal organ for alcohol metabolism. The body
naturally recognizes ethanol alcohol as a foreign, toxic agent that
can disrupt normal homeostasis.
When ethanol is consumed, it is rapidly absorbed by the upper
gastrointestinal tract. Ethanol is diffused throughout the body, but
exposure is greatest to the liver, via the main portal vein. Ethanol
is metabolized by the body in the gastric mucosa and the liver.
These organs manage an enzyme referred to as alcohol
dehydrogenase, which is used by the body to oxidize ethanol and
convert it into acetaldehyde and other metabolites. Acetaldehyde
ultimately is converted by the body into acetic acid, and then
acetate. Acetaldehyde affects protein synthesis.
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.
• Humans 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.
Alcohol
Alcohol
Microbial ADH
• Tetramer
• 4 x 352 amino acid
residues
• 4 zinc ions (Zn++)
• 4 NAD cofactors
Human ADH
• Homodimer (two
molecules)
• 2 x 373 amino acid
residues
• 6 zinc ions (Zn++)
• 2 NAD cofactors
Human
ADH
Microbial
Small Amounts
Unmetabolized (10%)
Excreted with
 Sweat
 Urine
 Breath
1st Pass Metabolism



Occurs in the Stomach
Gender Differences Exist: Men have a higher
level of ADH than women
Early metabolism translates to lower Blood
Alcohol (BAC) levels
2nd Pass Metabolism

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

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

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The Ratio of Alcohol in the blood to the total
volume of blood expressed as %
The presumptive level of intoxication =
0.10%
FOR A 75 Kgs. Individual each drink = .02%
*One drink is 14 gm pure alcohol
PROBLEM

If an individual weighing 75 Kgs.
consumes 2 drinks per hour, what will
his/her BAC level be at the end of that
time?
SOLUTION
Hour 1: .02 + .02 = .04 - .02 = .02%
Hour 2: .02 + .02 = .04 - .02 + .02 = .04%
Hour 3: .02 + .02 = .04 - .02 + .04 = .06%
Hour 4: .02 + .02 = .04 - .02 + .06 = .08%
Hour 5: .02 + .02 = .04 - .02 + .06 = .10% DUI
ALCOHOL’S EFFECT ON
THE BODY

DIGESTIVE SYSTEM:
• IRRITANT
• INCREASING AMOUNTS DISTRUPT OR
STOP DIGESTION
• PYLORIC VALVE MAY BE EFFECTED
“STUCK”
ALCOHOL’S EFFECT ON
THE BODY

CIRCULATORY SYSTEM
• MINOR EFFECTS
• Heartbeat & blood pressure little effect,
unless….
• 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 .02 little change
2 dk/hr .05 drinker high, judgement
center of brain affected, inhibitions
lowered
3 dk/hr .10 judgement is nil, muscle
coordination depressed, stagger, slur
speech

ALCOHOL’S EFFECT ON
THE BODY
10 dk/hr
0.20 emotions erratic, poor
memory
1 pint/hr 0.25 - 0.30 stuporous, judgement
long gone, coordination wiped out, sensory
perception almost gone
1.25 pints/hr 0.40 coma, brain center which
controls heart & lungs partially anesthetized
ALCOHOL’S EFFECT ON
THE BODY
0.40 - 0.50
coma
0.60
death
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.
Breaking Down Alcohol
Alcohol dehydrogenase
CH3CH2OH
+ 2 NAD
alcohol
(ethanol)

cofactor
CH3CHO
+ 2 NADH
aldehyde
(acetaldehyde)
cofactor
Acetaldehyde dehydrogenase 2
CH3CHO
aldehyde
(acetaldehyde)
+ H2O

CH3COOH
acid
(acetic acid or vinegar)
Breaking Down Alcohol
Acetaldehyde dehydrogenase 2
CH3CHO
aldehyde
(acetaldehyde)
+ H2 O

CH3COOH
acid
(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.
Via TCA
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 (denaturing) 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.
There have been studies showing that ADH
may have an influence on the dependence on
ethanol metabolism in alcoholics. Researchers
have tentatively detected a few genes to be
associated with alcoholism. If the variants of
these genes encode slower metabolizing forms
of ADH2 and ADH3, there is increased risk of
alcoholism. The studies have found that
mutations of ADH2 and ADH3 are related to
alcoholism in Northeast Asian populations
Breaking Down Methanol
Alcohol dehydrogenase
CH3CH2OH
+ 2 NAD
alcohol
(ethanol)

cofactor
CH3CHO
+ 2 NADH
aldehyde
(acetaldehyde)
cofactor
Alcohol dehydrogenase
CH3OH
alcohol
(methanol)
+
2 NAD
cofactor

CH2O
+ 2 NADH
aldehyde
(formaldehyde)
cofactor
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
b3 form
• The s 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.
Drink responsibly
Do Not Drink and Drive
Thank you