Alcohol Metabolism

Question 1

Overview of alcohol metabolism: 2 steps

Answer 1

1. Oxidation of ethanol to acetaldehyde (by alcohol dehydrogenase)
2. Oxidation of acetaldehyde to acetate (by acetaldehyde dehydrogenase)

Question 2

Alcohol Dehydrogenase (ADH)

Answer 2

• Converts ethanol to acetaldehyde
• Produces NADH
• Located in cytosol

Question 3

Consequences of acetaldehyde

Answer 3

• If not further metabolized can damage the liver

- May enter the blood and exert other toxic effects on tissues

Question 4

Acetaldehyde dehydrogenase (ALDH)

Answer 4

• Metabolizes about 90% of acetaldehyde
• Produces acetate and NADH
• Located in mitochondria
• ALDH2 is the major isozyme (mitochondrial)
• ALDH1 is cytosolic

Question 5

Fate of acetate produced by ALDH

Answer 5

-Enters blood and is converted to acetyl CoA

Question 6

MEOS

Answer 6

• Alternate route of alcohol metabolism
• Occurs in liver, microsomal alcohol oxidizing system
• CYP2E1 enzyme
• Converts ethanol to acetaldehyde using NADPH as an e donor and O2 as an e acceptor

Question 7

ADH isozymes

Answer 7

• ADH1 family have the highest affinity (lowest Km) for ethanol
• ADH1s can form homo or hetero dimers with each other but not with other ADH isozymes
• ADH1 mostly in liver
• ADH2 in liver and lower GI tract
• ADH3 inactive toward ethanol but active toward long chain alcohols
• ADH4 present in upper GI tract (gastric ADH)

Question 8

Consequences of inactive ALDH2

Answer 8

• Flushing, nausea, vomiting, distaste for alcohol

- ALDH2 inhibitors (disulfiram) may be given to alcoholics

Question 9

Acetyl CoA Synthetase

Answer 9

• Metabolism of acetate to acetyl CoA
• Primary isoform is ACS1 (cytosolic)–generates Acetyl CoA for cholesterol and fatty acid synthesis
• ACS2 allows other tissues to take up acetate and then use the acetyl coA for the TCA cycle and oxidation to CO2

Question 10

Cytochrome P450 major components

Answer 10

• Cytochrome p450 reductase–transfers electrons via FAD and FMN from NADPH
• Cytochrome p450–contains binding sites for O2 and substrate

Question 11

CYP2E1

Answer 11

• Cytochrome p450 mixed function oxidase
• Higher Km for ethanol than ADH1 so more involved when large quantities of alcohol are consumed
• Products: acetaldehyde and ROS (oxidative stress and cellular damage)
• Produces acetaldehyde faster than ALDH can handle in alcoholics–damage to liver and other tissues

Question 12

Acute effects on lipid metabolism in the liver

Answer 12

• Inhibition of FA synthesis
• Stimulation of TAG synthesis (leads to fatty liver)
• Ketoacidosis or lactic acidosis
• Caused by increased NADH/NAD ratio

Question 13

Mechanism of effect on lipid metabolism

Answer 13

1. Ethanol oxidation increases NADH/NAD ratio
2. Inhibits FA oxidation and TCA cycle leading to accumulation of FFAs
3. FAs reesterified to glycerol-3-p in ER. TAGS converted to VLDL and accumulate in liver
4. FAs that are oxidized are converted to acetyl CoA and ketone bodies
5. TCA cycle inhibition causes acetyl CoA to enter ketone body pathway
6. Increased production of lactate
7. Decreased uric acid excretion
8. Pyruvate converted to lactate and cannot be used for gluconeogenesis.

Question 14

Effects of chronic alcohol consumption

Answer 14

1. Acetaldehyde forms adducts with amino acids, decreases protein synthesis.
2. Protein accumulation causes swelling of liver and cell damage
3. Acetaldehyde forms adduct with GSH and other antioxidants–cannot protect agains ROS
4. MEOS induction increased ROS production, lipid peroxidation, and cell damage
5. Inhibition of electron transport
6. Protein loss of function–don’t secrete things out of the liver like they should.