Alcohol metabolism

Question 1

How is Ethanol converted to Acetate, what enzymes are involved and where are each located?

Answer 1

Ethanol –> Acetaldehyde occurs in the cytosol by alcohol dehydrogenase(ADH)

Acetaldehyde–> Acetate occurs in the mito by acetaldehyde dehydrogenase(ALDH)

Both produce NADH

Question 2

What is another route for alcohol metabolism in the liver?

Answer 2

MEOS–located in the ER

Question 3

What is the mechanism used by MEOS to convert ethanol to acetaldehyde? and when is it utilized?

Answer 3

CYP2E1–converts ethanol to acetaldehyde using NADPH as additional electron donor and O2 as electron acceptor

route accounts for 10-20% of ethanol oxidation in a moderate drinker

Question 4

What ADH has the highest affinity (lowest Km) for ethanol?

Answer 4

ADH1 family

Question 5

Where is ADH1 found and what is its characteristic?

Answer 5

present at high levels in liver and has highest affinity for ethanol

Question 6

Where is ADH2 found?

Answer 6

Liver and lower GI

Question 7

Where is ADH3 found and why is it different from ADH1 and 2?

Answer 7

present in many tissues

inactive toward ethanol–active toward long chain alcohols

Question 8

Where is ADH4 found and what may it contribute to?

Answer 8

upper GI

@ high ethanol concentration in upper GI
ADH4–> ethanol to acetaldehyde and my contribute to risk of cancer in heavy drinkers

Question 9

What form of ALDH is major form in liver and where is it located?

Answer 9

ALDH2 and has high affinity for acetaldehyde

Located in mito

Question 10

What is the cytoplasmic isozyme of ALDH?

Answer 10

ALDH1

Question 11

What is ALDH2*2 and what does it cause?

Answer 11

Single amino acid substitution Glu-Lys—leads to allelic variant with 23 fold higher Km and 35 fold lower Vmax

Homozygosity for this allele provides absolute protection against alcoholism

Question 12

What is used to convert acetate–> acetyl CoA?

Answer 12

Acetyl CoA synthetase

Question 13

What is the primary isoform of acetyl CoA synthetase (ACS) in the liver, is it cytosolic or mito and what controls its utilization? What is this acetyl CoA used for?

Answer 13

ACSI–cytosolic

acetate entry into cytosolic pathways is regulated by cholesterol and insulin

used for cholesterol and fatty acid synthesis

Question 14

What is the primary isoform of ACS in heart and skeletal muscle and is it cytosolic or mito?

What is this acetyl CoA used for?

Answer 14

ACSII– mito—enters the TCA cycle and is oxidized to CO2

Question 15

Does CYP2E1 have a higher or lower Km compared to ADH1? How does this come into play when large amounts of ETOH are consumed?

Answer 15

CYP2E1 has much higher Km—becomes more involved in ETOH oxidation when large quantities are consumed

Question 16

What are the products of ETOH oxidation by CYP2E1?

Whats the result?

Answer 16

Acetaldehyde and ROS–which results in oxidative stress and cellular damage

CYP2E1 induction increases ETOH clearance from the blood but produces acetaldehyde much faster than the liver ALDH can metabolize it–resulting in liver damage

Question 17

What are the factors that influence differences in alcoholism?

Answer 17

Genotypes–ADHs/ALDHs/CYP2E1s
Drinking Hx– Gastric ADH decreases and CYP2E1 increases with increasing drinking
Gender– Lower gastric ADH activity in women compared to men
Quantity of ethanol–CYP2E1 utilization increases with increasing drinking–increases acetaldehyde production

Question 18

What are the acute effects on liver metabolism?

Answer 18

Inhibition of fatty acid oxidation
stimulation of TAG synthesis–fatty liver (hepatic steatosis)
Ketoacidosis/lactic acidosis–causing hypo/hyperglycermia depending on dietary state

all considered reversible

Question 19

What does chronic ETOH consumption lead to?

Answer 19

increased acetaldehyde and ROS in the liver and released into the blood

• decreased protein synthesis
• accumulation of proteins–causing water to enter hepatocytes–portal HTN—increased ALT and AST
• acetaldehyde forms adduct with GSH–cannot protect against ROS
• MEOS increase ROS production