DR.

EMANUEL F CUMMINGS
READER IN BIOCHEMISTRY MOLECULAR
MEDICINE AND GENETICS
SCHOOL OF MEDICINE AND DENTISTRY

ALCOHOL AND ITS EFFECTS ON

METABOLISM
 INTRODUCTION

• ALCOHOL WIDELY UNDERSTOOD AS ( ETHANOL) C2H5OH

• HOWEVER THE TERM ALCOHOL CONSIST OF A WIDE
RANGE OF CHEMICALS THAT CONTAIN THE OH GROUP.
• MANY ALCOHOLIC DRINKS CONTAIN SMALL QUANTITIES
OF METHANOL CH3OH WHICH METABOLIZES TO
FORMALDEHYDE AND FORMIC ACID ( MORE TOXIC THAN
ETHANOL – BLINDNESS AND DEATH RAPIDLY.
 INTRODUCTION

• ETHANOL CONSUMPTION ACCOUNTS FOR 6% OF

TOTAL ENERGY INPUT IN THE UK.
• SIGNIFICANT AMOUNT OF PERSONS TAKING A
LARGE PROPORTION OF THEIR ENERGY (15-25%) AS
ALCOHOL
• ALCOHOL IS CONSIDERED TO BE FOOD AND IS USED
IN PREFERENCE TO OTHER NUTRIENTS.
• THE EFFECTS OF ALCOHOL ON THE CNS IS WELL
DOCUMENTED.
Standard-Sized Drinks
A Can of Beer
12 ounces of fluid @ 4% alcohol equals
0.48 ounces of pure ethanol
A Glass of Wine
5 ounces of fluid @ 12% alcohol equals
0.48 ounces of pure ethanol
A Shot of Whiskey (80-Proof)
1 and 1/4 ounces @ 40% alcohol equals
0.50 ounces of pure ethanol

II-16
 What is equal to what?
12 oz Beer = 4 oz Wine = 1 oz Liquor

= =
 Blood Alcohol Level

What does it mean?

BAL is the number of grams of alcohol
found in
100 milliliters of the person’s blood

Example
If a person has a BAL of .10%, then
there is one-tenth of a gram of alcohol
in every 100 milliliters of the person’s
blood.
II-23
Calculating BALs

 BALs are given in milligrams (mg) per 100

milliliters (ml) of whole blood
 Convert weight (e.g., 100 lbs) to kilograms
by dividing by 2.2 (1 kg = 2.2 lb)
 This weight is adjusted because not all of
the body is capable of absorbing alcohol
(75% in men and 66% in women)
 Convert alcohol to milligrams
 Divide the mg of alcohol/ml of body fluid x
100
• THE EFFECTS OF ALCOHOL VARY DEPENDING ON
MANY FACTORS

• PREVIOUS EXPERIENCE
• AMOUNT CONSUMED IN A GIVEN TIME PERIOD
• DRINKER'S SIZE, BODY BUILD, AND
METABOLISM
• TYPE AND AMOUNT OF FOOD IN THE STOMACH
• GENDER
 HOW MUCH IS TOO MUCH

• IMPAIRMENT BEGINS WITH THE FIRST DRINK.

• BALS VARY FROM PERSON TO PERSON DUE TO FACTORS
SUCH AS WEIGHT AND STOMACH CONTENTS.
• INDIVIDUALS CAN BE SUBSTANTIALLY IMPAIRED AFTER
TWO DRINKS.
• THE SAME AMOUNT OF ALCOHOL WILL RESULT IN
DIFFERENT BAL FOR MEN AND WOMEN.
 ABSORPTION

• ALCOHOL IS READILY ABSORBED FROM THE

GASTROINTESTINAL TRACT;
• HOWEVER, ALCOHOL CANNOT BE STORED AND
THEREFORE, THE BODY MUST OXIDIZE IT TO GET RID OF IT.
• ALCOHOL CAN ONLY BE OXIDIZED IN THE LIVER, WHERE
ENZYMES ARE FOUND TO INITIATE THE PROCESS.
• IN ADDITION, ALCOHOL DIRECTLY CONTRIBUTES TO
MALNUTRITION SINCE A PINT OF 86 PROOF ALCOHOL
(NOT AN UNUSUAL DAILY INTAKE FOR AN ALCOHOLIC)
REPRESENTS ABOUT HALF OF THE DAILY ENERGY
REQUIREMENT.
 ABSORPTION

• HOWEVER, ETHANOL DOES NOT HAVE ANY

MINERALS, VITAMINS, CARBOHYDRATES, FATS OR
PROTEIN ASSOCIATED WITH IT.
• ALCOHOL CAUSES INFLAMMATION OF THE
STOMACH, PANCREAS, AND INTESTINES WHICH
IMPAIRS THE DIGESTION OF FOOD AND
ABSORPTION INTO BLOOD.
• MOREOVER, THE ACETALDEHYDE (THE OXIDATION
PRODUCT) CAN INTERFERE WITH THE ACTIVATION
OF VITAMINS.
 Distribution of Alcohol

Getting the ethanol into the body’s tissues

and organs

Basic Principle

Ethanol goes wherever it finds water

II-19
 Which Organs of the Body have
Lots of Water?

The Brain; The Liver; Muscle Tissue

Which Organs don’t ?

Bones; Fatty Tissue
The average male is 68 percent water
The average female is only 55 percent water

II-20
Metabolism
 Both water soluble and lipid soluble
 Absorbed through lining of digestive tract
 Follows zero-order kinetics for elimination
 5-15% excreted un-metabolized through exhaled breath,
sweat, urine and skin
 85-95% metabolized in liver
 Build up of acetaldehyde leads to “flushing response”

Ethanol Acetaldehyde Acetate

Alcohol Aldehyde
Dehydrogenase Dehydrogenase
 METABOLISM

• ABOUT 80 % OF THE ACETATE PRODUCED BY THE LIVER LEAVES THE

LIVER AND UNDERGOES FURTHER METABOLISM IN TISSUES SUCH AS
HEART AND SKELETAL MUSCLE.
• EXPERIMENTS HAVE SHOWN THAT THE ACETATE CAN ONLY BE
CONVERTED TO FATTY ACIDS, CHOLESTEROL AND AMINO ACIDS AND
NOT REALLY ATP VIA THE KREBS CYCLE
 DISULFIRAM

• KINETIC STUDIES HAVE SHOWN THAT THE ENZYME

ALDEHYDE DEHYDROGENASE PLAYS THE DOMINANT
ROLE IN ALCOHOL METABOLISM
• IS INHIBITED BY DISULFIRAM (USED IN TTO
ALCOHOLISM )
• DISULFIRAM IS RESPONSIBLE FOR THE UNPLEASANT
REACTIONS SUCH AS- FACIAL FLUSHING, HEADACHE,
AND NAUSEA AFTER INGESTION OF SMALL AMOUNTS
OF ALCOHOL.
• DUE TO THE ACCUMULATION OF ACETALDEHYDE
Metabolism
 Another system of alcohol metabolism: microsomal ethanol-
oxidizing system (MEOS) – involved in the metabolism of
barbiturates.
 Alcohol dehydrogenase saturates at low to moderate
BALs (Michaelis-Menten kinetics)
 Apparent zero-order kinetics at moderate BALs

 Alcohol Elimination Rate = 7 g per hr

 Disappearance Rate = 0.015% per hr

 Histamine receptor antagonists (e.g., Tagmet and Zantac),

typically used to reduce stomach acidity, also reduce levels
of alcohol dehydrogenase, increasing BAL.
 CYTOCHROME P450

• CYTOCHROME P 450 IS ALSO INVOLVED IN THE METABOLISM OF

VARIOUS DRUGS.
• CONSUMPTION OF ALCOHOL INCREASES THE CONCENTRATION OF
MANY DRUGS BY COMPETITION
• STUDIES HAVE SHOWN THAT THIS MICROSOMAL SYSTEM IS
INCREASED BY CHRONIC ADMINISTRATION OF ALCOHOL. (
TOLERANCE), FORMATION OF POTENTIAL CARCINOGENS IN
ALCOHOLICS
 HOW MUCH IS TOO MUCH

• IMPAIRMENT BEGINS WITH THE FIRST DRINK.

• BALS VARY FROM PERSON TO PERSON DUE TO FACTORS
SUCH AS WEIGHT AND STOMACH CONTENTS.
• INDIVIDUALS CAN BE SUBSTANTIALLY IMPAIRED AFTER
TWO DRINKS.
• THE SAME AMOUNT OF ALCOHOL WILL RESULT IN
DIFFERENT BAL FOR MEN AND WOMEN.
 METABOLISM

• GENDER DIFFERENCES EXIST:

• MEN HAVE A > LEVEL OF ADH THAN WOMEN
• THE SAME AMOUNT OF ALCOHOL WILL RESULT IN
DIFFERENT BAL FOR MEN AND WOMEN BECAUSE
ALCOHOL IS PROCESSED DIFFERENTLY BY MEN AND
WOMEN
• EARLY METABOLISM TRANSLATES TO LOWER BAL LEVELS
 GENDER DIFFERENCES

• MEN'S BODIES TYPICALLY CONTAIN MORE BODY WATER (61% VS 52%)

• IF YOU ARE HYDRATED, THE MORE YOU WEIGH THE MORE WATER YOUR
BODY WILL HAVE TO DILUTE ALCOHOL. THIS CAN SLOW ABSORPTION
• HENCE WILL BE ABLE TO DILUTE THE ALCOHOL MORE.
• A 165-LB MALE WHO HAS HAD FOUR STANDARD BEERS IN ONE HOUR
WILL HAVE AN ESTIMATED BAL OF 0.082%.
• A 130 LB FEMALE IN AN HOUR, WILL HAVE A BAL OF ABOUT 0.123%.
 ETHNICITY

• SOME ASIANS HAVE A MALFUNCTIONING ALDEHYDE

DEHYDROGENASE ENZYME
• COMPARING OF CAUCASIANS AND ORIENTALS THERE IS A MARKED
ABSENCE OF ACETALDEHYDE IN CAUCASIANS AS TO A MARKED
ELEVATION IN OREINTALS AFTER INGFESTION OF ALCOHOL.
• THE AFFECTED INDIVIDUALS POSSESS A VARIANT ALCOHOL
DEHYDROGENASE IN THE LIVER MITOCHONDRIA WHICH
METABOLIZES THE ACETALDEHYDE MORE SLOWLY. (SINGLE AMINO
ACID SUBS NEAR THE C TERMINAL
 OTHER FACTORS

• YOUR WEIGHT WILL AFFECT WHAT YOUR ESTIMATED BAL I

• ALCOHOL IS ABSORBED THROUGH MUSCLE TISSUE AND NOT FAT.
• THE MORE BODY FAT YOU HAVE, THE HIGHER YOUR BAL WILL BE
• A MAN WHO WEIGHS 180 POUNDS BUT IS IN GOOD SHAPE WILL
TYPICALLY HAVE A LOWER BAC THAN A MAN WEIGHING 180
POUNDS WHO IS OUT OF SHAPE.
• AGE-. AS WE AGE OUR METABOLISM SLOWS DOWN AND OUR
BODIES MAY NOT PROCESS ALCOHOL AS QUICKLY
 INTOXICATION

• FACIAL FLUSHING AND INCREASE HEART RATE IS A

CONSEQUENCE OF ALCOHOL INGESTION IN MOST
INDIVIDUALS.
 NADH/NAD RATIO

• A SIGNIFICANT ASPECT OF ETHANOL METABOLISM IS ITS

ACTION ON THE REDOX LEVELS OF THE CYTOSOL AND
MITOCHONDRIA OF LIVER CELLS
• NADH IS GENERATED IN THE OXIDATION OF ETHANOL.
• CAN BE REOXIDIZED TO NAD BY A VARIETY OF REACTIONS
SUCH AS PYRUVATE TO LACTATE, AND THE CONVERSION OF
1,3 BPG TO G3P
• A CHARACTERISTIC EFFECT OF ETHANOL IS TO CHANGE THE
RATIO OF FREE NAD TO FREE NADH IN THE CYTOSOL , 3 TO 4
FOLD INCREASE IN FREE CYSTOLIC NADH AND A
CORRESPONDING DECREASE IN FREE NAD
 METABOLIC FATES OF NADH

• 1. PYRUVIC ACID TO LACTIC ACID: ( LACTIC ACIDOSIS)

• THE CONVERSION OF PYRUVIC ACID TO LACTIC ACID REQUIRES
NADH:
• PYRUVIC ACID + NADH + H+ ---> LACTIC ACID + NAD+
• THIS PYRUVIC ACID NORMALLY MADE BY TRANSAMINATION OF
AMINO ACIDS, IS INTENDED FOR CONVERSION INTO GLUCOSE BY
GLUCONEOGENESIS.
• THIS PATHWAY IS INHIBITED BY LOW CONCENTRATIONS OF PYRUVIC
ACID, SINCE IT HAS BEEN CONVERTED TO LACTIC ACID.
• THE FINAL RESULT MAY BE ACIDOSIS FROM LACTIC ACID BUILD-UP
AND HYPOGLYCEMIA FROM LACK OF GLUCOSE SYNTHESIS.
• 2. SYNTHESIS OF LIPIDS:
• EXCESS NADH MAY BE USED AS A REDUCING AGENT IN TWO PATHWAYS--ONE
TO SYNTHESIZE GLYCEROL (FROM A GLYCOLYSIS INTERMEDIATE) AND THE OTHER
TO SYNTHESIS FATTY ACIDS. AS A RESULT, HEAVY DRINKERS MAY INITIALLY BE
OVERWEIGHT.
• 3. ELECTRON TRANSPORT CHAIN:
• THE NADH MAY BE USED DIRECTLY IN THE ELECTRON TRANSPORT CHAIN TO
SYNTHESIZE ATP AS A SOURCE OF ENERGY.
• THIS REACTION HAS THE DIRECT EFFECT OF INHIBITING THE NORMAL OXIDATION
OF FATS IN THE FATTY ACID SPIRAL AND CITRIC ACID CYCLE. FATS MAY
ACCUMULATE OR ACETYL COA MAY ACCUMULATE WITH THE RESULTING
PRODUCTION OF KETONE BODIES.
• ACCUMULATION OF FAT IN THE LIVER CAN BE ALLEVIATED BY SECRETING LIPIDS
INTO THE BLOOD STREAM.
• THE HIGHER LIPID LEVELS IN THE BLOOD MAY BE RESPONSIBLE FOR HEART
ATTACKS.
 HYPOGLYCAEMIC EFFECTS

• ASSOCIATED WITH MALNOURISHED CHRONIC ALCOHOLICS.

• HYPOGLYCAEMIA CAUSES INADEQUATE SUPPLY OF GLUCOSE TO THE BRAIN DERANGEMENT OF
CEREBRAL FUNCTION AND DEATH.
• THE HIGH VALUE OF NADH/NAD RATIO IN LIVER IS PROBABLY THE FACTOR THAT SUPPRESSES
GLUCONEOGENESIS BY:
1- INCREASE IN NADH/NAD RATIO SUPPRESS SEVERAL OXIDATION REACTIONS OF THE CITRIC ACID
CYCLE.
2- DECREASE IN THE CONVERSION OF LACTATE TO PYRUVATE
3- REDUCTION IN THE FORMATION OF DHAP FROM G3P.
4- INHIBITION OF GALACTOSE TO GLUCOSE
5- INCREASE IN FATTY ACID OXIDATION.
 EFFECTS ON PLASMA LIPIDS

• ALCOHOL INGESTION CAUSES SEVERE HYPERLIPIDEMIA

• DAILY DRINKERS INCREASE IN TAG COMPARED TO ABSTAINERS.
• ALCOHOL IS FOOD AND IS OXIDIZED IN PREFERENCE TO ALL OTHER SUBSTRATES
IN THE LIVER, THUS DECREASING THE OXIDATION OF FATTY ACIDS AND GLUCOSE.
• DECREASE IN THE OXIDATION OF FATTY ACID ENTERING THE LIVER CAUSES
PROPORTIONAL INCREASE IN THE SYNTHESIS OF TAG (VLDL)
• RISE IN PLASMA TAG
• SOME OF THE TAG IS RETAINED BY THE LIVER RESULTING IN FATTY LIVER.
• FATTY LIVER CAN LEAD TO CIRRHOSIS.
 EFFECTS ON VITAMINS REQIUREMENTS

• ALCOHOLISM IS A MAJOR CAUSE OF MALNUTRITION IN COUNTRIES

WITH AN ADEQUATE FOOD SUPPLY.
• DIETS OF MANY ALCOHOLICS IS POOR IN VITAMINS AND MINERALS
• CHRONIC INGESTION OF ALCOHOL LEADS TO INCREASE
REQUIREMENTS OF VITAMINS ON ONE HAND AND POOR
ABSORPTION ON THE OTHER HAND
• THERE IS ALSO DECREASE STORAGE AND INCREASE BREAKDOWN
AND MAY DEVELOP DEFICENCIES OF B1, B6, AND B12 AND FOLATE.
 OTHER EFFECTS

• ALCOHOLISM EFFECTS: A CENTRAL ROLE IN THE TOXICITY OF

ALCOHOL MAY BE PLAYED BY ACETALDEHYDE ITSELF.
• ALTHOUGH THE LIVER CONVERTS ACETALDEHYDE INTO ACETIC
ACID, IT REACHES A SATURATION POINT WHERE SOME OF IT
ESCAPES INTO THE BLOOD STREAM.
• THE ACCUMULATED ACETALDEHYDE EXERTS ITS TOXIC EFFECTS
BY INHIBITING THE MITOCHONDRIA REACTIONS AND
FUNCTIONS.
• THE ALCOHOLIC IS A VICTIM OF A VICIOUS CIRCLE; A HIGH
ACETALDEHYDE LEVEL IMPAIRS MITOCHONDRIA FUNCTION,
METABOLISM OF ACETALDEHYDE TO ACETIC ACID DECREASES,
MORE ACETALDEHYDE ACCUMULATES, AND CAUSES FURTHER
LIVER DAMAGE--HEPATITIS AND CIRRHOSIS.
 NOTE

• RECENT INVESTIGATIONS HAVE SUGGESTED THAT

ACETALDEHYDE MAY BE RESPONSIBLE FOR THE
DEVELOPMENT OF ALCOHOL ADDICTION.
• ACETALDEHYDE IN THE BRAIN MAY INHIBIT ENZYMES
DESIGNED TO CONVERT CERTAIN NERVE
TRANSMITTERS FROM ALDEHYDES TO ACIDS.
• THE NERVE TRANSMITTERS THAT ACCUMULATE MAY
THEN REACT WITH THE ACETALDEHYDE TO FORM
COMPOUNDS WHICH ARE STARTLINGLY SIMILAR TO
CERTAIN MORPHINE-TYPE COMPOUNDS
Alcohol and the GABA Receptor

 When alcohol enters the brain, it binds to

GABA receptors and amplifies the
hyperpolarization effect of GABA.
 The neuron activity is further diminished
 This accounts for some of the sedative
affects of alcohol

science.howstuffworks.com/ alcohol.htm
Tolerance
 Behavior
 commonly half the level of behavioral intoxication at same blood
alcohol level of nontolerant individuals
 environment-dependent tolerance
 learned tolerance

 Pharmacokinetic Mechanism
 liver increases enzyme levels
 accounts for up to 25% of tolerance

 Pharmacodynamic mechanisms
 changes in NMDA and GABAa receptors as per chronic effects
 WITHDRAWAL
• EXCITATORY/INHIBITORY AMINO ACID IMBALANCE
• HYPEREXCITABILITY
• SEIZURES
• DELIRIUM TREMENS (DTS) - 5% OF PATIENTS DEVELOP IT AND A 35%
MORTALITY RATE IF UNTREATED
• RAPID HEART RATE - TREMORS
• INCREASED BODY TEMPERATURE - HALLUCINATIONS
• INCREASED BLOOD PRESSURE - SWEATING
• PSYCHOMOTOR AGITATION - LOSS OF ABILITY TO CONTROL MUSCLE
MOVEMENT
• CONFUSION - INCREASED BLOOD PRESSURE
• CARDIOVASCULAR COLLAPSE AND DEATH
• DISORIENTATION - ALTERED MENTAL STATUS
• SLEEP DISORDERS

• DYSFUNCTIONAL MONOAMINE SYSTEMS

• DEPRESSION
Positive Effects of Moderate Doses
(1-2 drinks/day)

 Pleasurable

 Anxiolytic (relieves anxiety and

depression)

 Increases socialization (“the

social lubricant”)

 Lowers mortality rate relative to

non-drinkers
 probably due to elevating HDL
(“good” cholesterol)

 Increases levels of estrogen

(easing postmenopausal
symptoms)
 POSITIVE EFFECTS OF MODERATE DOSES(1-2
Pleasurable DRINKS/DAY)
Anxiolytic (relieves anxiety and depression)

Increases socialization (“the social lubricant”)

Lowers mortality rate relative to non-drinkers

probably due to elevating HDL (“good” cholesterol)

Increases levels of estrogen (easing postmenopausal symptoms)

Negative Effects of High-level Consumption

 Reduced sex drive

 Shrinking brain, enlarged
ventricles
 High blood pressure
 Cirrhosis of the liver
 Peripheral Neuropathy
 Korsakoff’s Syndrome
 Depression
 Decreased brain glucose
metabolism
 Fetal Alcohol Spectrum Disorders

A. Magnetic resonance imaging showing the side view of a 14-year-old control subject with a normal corpus callosum; B. 12-year-old with FAS
and a thin corpus callosum; C. 14-year-old with FAS and agenesis (absence due to abnormal development) of the corpus callosum.
Source: Mattson, S.N.; Jernigan, T.L.; and Riley, E.P. 1994. MRI and prenatal alcohol exposure: Images provide insight into FAS. Alcohol
Health & Research World 18(1):49–52.
GENERAL EFFECTS OF ALCOHOL
Acute Cognitive Impairments
White et al., 1998

 Memory formation
 Attention (divided, selective)
 Reaction time
 Visual search and tracking
 Abstract thinking
 Problem solving/flexibility
 Multi-tasking
 “Alcohol myopia”
 Impaired judgement of abilities
 PHARMACOTHERAPIES

• BENZODIAZEPINES
• FOR ACUTE WITHDRAWAL

• DISULFIRAM (ANTABUSE)
• INTERFERES WITH ALCOHOL METABOLISM
• CAUSES AVERSIVE REACTION (LIKE FLUSHING RESPONSE)

• NALTREXONE
• OPIOID ANTAGONIST
• SUPPOSED TO DECREASE CRAVING
• EFFICACY STILL UNDER DEBATE
 ASSIGNMENT/ READ

• MALONDIALDEHYDE-ACETALDEHYDE (MAA) PROTEIN ADDUCTS

ARE FOUND EXCLUSIVELY IN THE LUNGS OF SMOKERS WITH
ALCOHOL USE DISORDERS AND ARE ASSOCIATED WITH SYSTEMIC
ANTI-MAA ANTIBODIES.
• MALONDIALDEHYDE (MDA) AND ACETALDEHYDE (AA) EXIST
FOLLOWING ETHANOL METABOLISM AND TOBACCO