Lecture 7 - alcohol metabolism

Question 1

What are in alcoholic beverages ?

Answer 1

Water, ethanol and sugar

Question 2

How is alcohol absorbed?

Answer 2

It is rapidly absorbed by simple diffusion in the GI tract. About 20 % is absorbed in the stomach and this absorbed alcohol is quickly spread to water compartments around the body.

Question 3

How is alcohol metabolised and excreted (with percentages)?

Answer 3

90% is metabolised by the liver and 5% is excreted into the urine. The remainder 5% is eliminated by the lungs which is the basis of the breathalyser test.

Question 4

What factors effect the blood alcohol level?

Answer 4

Weight - more weight = more body water so the alcohol becomes more dilute

Gender - men have more body water and more stomach ADH so lower blood alcohol level after drrinking.

Food - food in the stomach slows down alcohol absorption so the more food people eat the lower the blood alcohol level

Drinking Rate - body metabolises alcohol slowly, more drinks in an hour, higher blood alcohol level

Type of drink - amount of alcohol in a drink, when carbonated mixers are used the body absorbs alcohol faster.

Question 5

What are the pathways for ethanol metabolism?

Answer 5

1. ) cytosol alcohol dehydrogenase (ADH) - for beraking down small amounts of alcohol
2. ) Microsomal ethanol-oxidizing system (MEOS) - for breaking down large amounts of alcohol

Alcohol is also metabolised by colon bacterial ADH to yield acetaldehyde - a toxic compound

Question 6

How is ethanol used by the muscle ?

Answer 6

1. ) Ethanol
2. ) ADH
3. ) Acetaldehyde
4. ) Acetate by ALDH
5. ) Goes to muscles
6. ) Becomes acetyl CoA by ACS
7. ) Goes through TCA cycle for energy

Acetaldehyde goes to blood

Question 7

What does the metabolism of ethanol cause?

Answer 7

Results in massive increase in the concentratin of cytosolic NADH in the liver. This increase in NADH causes the intermediates of gluconeogenesis to be diverted into alternate rreaction pathways, resulting in decreased synthesis of glucose.

Question 8

Ethanol metabolism?

Answer 8

1. ) Ethanol
2. ) Acetaldehyde by alcohol dehydrogenase and this produces NADH
3. ) Acetaldehyde to acetate by aldehyde dehydrogenase, produces NADH

Question 9

What is Disulfiram ?

Answer 9

It blocks enzyme that converts acetaldhyde to acetate (aldehyde dehydrogenase) so there is a build og acetaldehyde causing a person to feel symptoms making them stop drinking.

Question 10

What is fomepizole ?

Answer 10

blocks alcohol dehydrogenase and is the preferred antidote for overdoes of methanol or ethylene glycol.

Question 11

Why can methanol be used as a competitive inhibitor to treat methanol or ethylene poisoning?

Answer 11

Because alcohol dehydrogenase has a higher affinity for ethanol than methanol or ethylene glycol. Essentially the alcohol dehydrogenase will go to ethanol instead of methanol or the other one.

Question 12

What are the different kinds of alcohol dehydrogenase?

Answer 12

Class 1 - high in the liver (3% of soluble protein). High affinity for alcohol so the liver is a major site for metabolism of alcohols and generation of toxic acetaldehyde.

Class IV - in the GIT and acetaldehye produced here may contribute to cancers of this system

Class 2 - primarily expressed in the liver and at a lower rate in the GI tract

Question 13

How many functional polymorphisms are there of Alcohol dehydrogenase?

Answer 13

three of them:

ADH 1A
ADH 1C

ADH1B*2 - encodes fast ADH and so decreased susceptibility to alcoholism - there will benausea and flushing caused by acetaldehyde accumulation. The ALDH cant keep up with ADH. With this you are less likely to be an alcoholic because you vomit fast and it is common in asians but low in white europeans.

Question 14

Kinds of acetaldehyde dehydrogenase (ALDH) ?

Answer 14

ALDH2 - 80% by mitochondrial ALDH
ALDH1 - cytosolic

poeple with ALDH2 have a greatly decreased capacity for acetaldehyde metabolism.

Question 15

What happens to the acetate?

Answer 15

metabolism requires the activation of the acetyl CoA cycle which requires acetyl CoA synthase (ACS).

ACS1 generates acetyl CoA for the cytosolic synthesis of cholestrol and FA.

Lots of acetate that goes to blood, goes to heart and skeletal muscle because there are high concentrations of ACS2 there.

Question 16

WHat does MEOS have?

Answer 16

members of cytochrome P450 superfamily of enzymes. Within these families there are 10 distinct gene families. MEOS is the combined ethanol oxidizing activity of all P450 enzymes.

Question 17

Why does a greater proportion of ethanol become metabolised in MEOS than with the ADH?

Answer 17

because CYP2E1 has a greater affinity for ethanol than class 1 ADHs.

Question 18

How are P450 enzymes induced?

Answer 18

With chronic consumption, CYP2E1 increases 5-10 fold. Also other P450 increase and so the ER proliferates.

Question 19

Effect of the increased NADH from ethanol metabolism?

Answer 19

1.) change in FA metabolism:
High ratio will inhibit the oxidation of FAs so they accumulate in the liver and form TAG. This promotes the synthesis of glycerol 3 P from glycolysis intermediates and TAGS become incorporated with VLDLs that accumulate in the liver and enter the blood. This results in ethanol induced hyperlipidemia.

2.) alcohol induced ketoacidosis:
FAs oxidized to acetyl-CoA and then to ketone bodies. Ketone bodies produced at a high rate and concentrations might even be higher than found under normal conditions.

3. ) lactic Acidosis, hyperuricemia and hypoglycemia:
   - Balance of LDH shifted to lactate which results in lactic acidosis
   - Thiis will decrease excretion of uric acid by kidney
   - Hypoglycemia caused because in a fasting individual who has been driniking, they are relying on gluconeogenesis to maintain blood sugar. Lactate amd alanine which are gluconeogenesis precursors enter as pyruvate and so the ratio shifts towards lactate and so they cannot enter.
   - hyperglycemia if the person has had a meal because of inhibition of glycolysis

Question 20

What is acetaldehyde toxicity?

Answer 20

Many toxic effects of chronic ethanol consumption results from an accumulation of acetaldehyde which is produced by both pathways of alcohol metabolism.

This is because it accumulates in the liver and is released into the blood. It is highly reactive and bonds covalently to amino acids, sulfhydryl groups, nucleotides, and phospholipids to form adducts.

Question 21

What is acetaldehyde and alcohol induced hepatitis?

Answer 21

Since acetalaldehyde adduct has a formation with AAs, this results in a decrease in hepatic protein synthesis. Proteins in the heart are also affected and this decreases tubulin synthesis which results in a diminished secretion of serum proteins and VLDL from the liver. Proteins accumulate in the liver along with lipids and this leads to influx of water in hepatocytes.

Question 22

What free radical damage does acetaldehyde cause?

Answer 22

Acetaldehyde adduct causes free radical damage by binding driectly to glutathione and this diminishes its ability to protect afainst H2O2 and prevent lipid peroxidation. This causes mitochondrial damage and ETC inhibited and FA oxidation decreased (lipids accumulate).

• This also increases oxiditative stress in the liver which arises from the increased production of free radicals by CYP2E1.
• Phospholipids are the primary target of peroxidation caused by the free radical release.

Question 23

What is hepatic cirrhosis?

Answer 23

It is a liver injury that is irreversible. The liver becomes enlarged, full of fat and crossed with collagen fibers. The normal metabolic processes are lost.

Question 24

What is laennec’s cirrhosis?

Answer 24

The liver is shrunken

Question 25

Why does alcoholism lead to a fatty liver?

Answer 25

Bc there are increased levels of NADh in the liver whihc inhibit the oxidation of fatty acids. Ability to secrete TAGs is diminished resulting in fatty liver.

Question 26

elevated ….. is frequently associated with chronic alcoholism?

Answer 26

VLDL

Question 27

Adverse effects of alcohol consumption?

Answer 27

Short term - interfere with organ function for several hours after ingestion.
Chronic alcohol consumption interferes with nutrritional status and produces toxic compounds.

Question 28

Acute effects of alcohol?

Answer 28

When alcohol intake exceeds the ability of teh lover to break it down than you can get alcohol intoxication or alcohol poisoning. The circulating alcohol affects the central nervous system, breathing and heart rate.