Chemical Pathology – Alcohol Abuse
- Ethanol is rapidly absorbed from the upper GIT
- It is then distributed in the total body water (plasma)
- Its elimination depends primarily on hepatic metabolism
- This is due to the fact that the enzymes catalyzing the
first 2 steps of ethanol oxidation is confined to the liver.
Metabolism of Alcohol:
- There are 3 main steps to alcohol metabolism:
1.) Ethanol → Acetaldehyde (oxidation)
2.) Acetaldehyde → Acetic Acid
3.) Acetic Acid → Acetyl CoA
1.) Oxidation of Ethanol to Acetaldehyde:
o This step can be accomplished by 3 different systems:
Alcohol Dehydrogenase Pathway
Alcohol Dehydrogenase (AD) is an enzyme (found in the cytosol) that is
saturated at low blood ethanol levels (i.e. it does not get induced by
alcohol intake and thus gets eliminated at a constant rate)
In this step, 2 H+ atoms are transferred from ethanol to NAD thus
forming NADH and acetaldehyde
Microsomal Ethanol Oxidizing System (MEOS)
This is a cytochrome P450 containing enzyme (CYP2E1)
It is found in the endoplasmic reticulum
Its synthesis is induced by chronic exposure to alcohol
It assumes increasing importance in high ethanol levels
It uses NADH and molecular oxygen to convert ethanol to acetaldehyde
Induction of CYP2E1 increases the liver’s capacity to oxidise other drugs
such as: propranolol, warfarin, diazepam, barbiturates and paracetamol
Catalase
Located in peroxisomes
It is of little importance in ethanol metabolism
2.) Second Step
- Acetaldehyde enters the mitochondria, where it is oxidized to acetic acid by aldehyde
dehydrogenase (ALD).
- The high activity of this enzyme ensures that acetaldehyde levels are kept to a minimum.
- As with AD, this step also generates NADH from NAD.
- Disulfiram (antabuse) is an inhibitor of ALD, and is used deliberately to help alcoholics abstain
o Ingestion of any ethanol by subjects taking disulfiram results in the acute discomfort of
acetaldehyde toxicity.
o Flagyl (metronidazole), an anti-microbial drug, has a similar effect.
- A common genetic polymorphism in Orientals, resulting in low ALD activity, explains the low
ethanol tolerance and low incidence of alcoholism among these populations.
, 3.) The Third Step:
- The third and final step in ethanol metabolism involves activation of acetic acid by co-enzyme A
to form acetyl CoA
- The Krebs cycle activity is limited by lack of NAD
- Hence the bulk of acetyl CoA formed is converted to fatty acids (or to ketone bodies - under
conditions of carbohydrate depletion)
- Activation of acetic acid requires hydrolysis of ATP to AMP. A fraction of the AMP escapes
recycling to ATP, and is degraded to uric acid.
Acute Derangements induced by ethanol ingestion:
- Ethanol is a rich source of energy.
- Enzymes required for the first 2 steps of its metabolism are confined to the liver, which thus
carries the full burden of its conversion to acetate.
- This results in a temporary but profound ethanol-induced imbalance in the ratio of NADH to
NAD, AND production of surplus acetyl CoA, in the liver.
- Many of the metabolic disturbances induced by ethanol can be traced back to either or both of
these two biochemical aberrations (NADH/NAD ratio and/or ↑ acetyl CoA).
- Ethanol is rapidly absorbed from the upper GIT
- It is then distributed in the total body water (plasma)
- Its elimination depends primarily on hepatic metabolism
- This is due to the fact that the enzymes catalyzing the
first 2 steps of ethanol oxidation is confined to the liver.
Metabolism of Alcohol:
- There are 3 main steps to alcohol metabolism:
1.) Ethanol → Acetaldehyde (oxidation)
2.) Acetaldehyde → Acetic Acid
3.) Acetic Acid → Acetyl CoA
1.) Oxidation of Ethanol to Acetaldehyde:
o This step can be accomplished by 3 different systems:
Alcohol Dehydrogenase Pathway
Alcohol Dehydrogenase (AD) is an enzyme (found in the cytosol) that is
saturated at low blood ethanol levels (i.e. it does not get induced by
alcohol intake and thus gets eliminated at a constant rate)
In this step, 2 H+ atoms are transferred from ethanol to NAD thus
forming NADH and acetaldehyde
Microsomal Ethanol Oxidizing System (MEOS)
This is a cytochrome P450 containing enzyme (CYP2E1)
It is found in the endoplasmic reticulum
Its synthesis is induced by chronic exposure to alcohol
It assumes increasing importance in high ethanol levels
It uses NADH and molecular oxygen to convert ethanol to acetaldehyde
Induction of CYP2E1 increases the liver’s capacity to oxidise other drugs
such as: propranolol, warfarin, diazepam, barbiturates and paracetamol
Catalase
Located in peroxisomes
It is of little importance in ethanol metabolism
2.) Second Step
- Acetaldehyde enters the mitochondria, where it is oxidized to acetic acid by aldehyde
dehydrogenase (ALD).
- The high activity of this enzyme ensures that acetaldehyde levels are kept to a minimum.
- As with AD, this step also generates NADH from NAD.
- Disulfiram (antabuse) is an inhibitor of ALD, and is used deliberately to help alcoholics abstain
o Ingestion of any ethanol by subjects taking disulfiram results in the acute discomfort of
acetaldehyde toxicity.
o Flagyl (metronidazole), an anti-microbial drug, has a similar effect.
- A common genetic polymorphism in Orientals, resulting in low ALD activity, explains the low
ethanol tolerance and low incidence of alcoholism among these populations.
, 3.) The Third Step:
- The third and final step in ethanol metabolism involves activation of acetic acid by co-enzyme A
to form acetyl CoA
- The Krebs cycle activity is limited by lack of NAD
- Hence the bulk of acetyl CoA formed is converted to fatty acids (or to ketone bodies - under
conditions of carbohydrate depletion)
- Activation of acetic acid requires hydrolysis of ATP to AMP. A fraction of the AMP escapes
recycling to ATP, and is degraded to uric acid.
Acute Derangements induced by ethanol ingestion:
- Ethanol is a rich source of energy.
- Enzymes required for the first 2 steps of its metabolism are confined to the liver, which thus
carries the full burden of its conversion to acetate.
- This results in a temporary but profound ethanol-induced imbalance in the ratio of NADH to
NAD, AND production of surplus acetyl CoA, in the liver.
- Many of the metabolic disturbances induced by ethanol can be traced back to either or both of
these two biochemical aberrations (NADH/NAD ratio and/or ↑ acetyl CoA).
