Ethanol metabolism

Question 1

What properties make ethanol able to diffuse through the GI wall so easily?

Answer 1

it is both lipid and water soluble

Question 2

What enzyme is primarily responsible for ethanol metabolism?

What molecule is produced from this reaction?

Answer 2

alcohol dehydrogenase in the liver

acetylaldehyde is produced, which can have toxic effects in the liver and other parts of the body as it enters the bloodstream

Question 3

What is the name of the enzyme that converts acetaldehyde to acetate?

What ration changes with increased use of this enzyme?

Answer 3

acetaldehyde dehydrogenase (ALDH)

the NADH/NAD ratio increases

Question 4

What is the second principle route for ethanol metabolism in the liver? What is the principle enzyme involved?

About what percent of all ethanol metabolism does this account for in a moderate drinker?

Answer 4

MEOS (mitochondrial ethanol oxidizing system)

cytochrome p450 oxidase isozyme (CYP2E1), which uses NADPH as additional electron donor and O2 as an electron acceptor

10-20% in a moderate drinker

Question 5

How many isozymes of ADH exist in the body? Which is most specific for ethanol?

Answer 5

6

ADH1 family (A,B, C)

Question 6

What is the clinical implication of patients who have the ALDH2*2 allelic variant?

Answer 6

decreased capacity for acetylaldehyde metabolism b/c increased Km and decreased Vmax

Question 7

Describe the distribution of ALDH

Answer 7

80% ALDH is in the mitochondria (ALDH2)–> high affinity

20% in the cytoplasm (ALDH1)

Question 8

What is the clinical significance of someone with the ADH1B*2 allele?

Answer 8

increased alcohol metabolism (high vmax)

decreased susceptibility to alcoholism–> ALDH cannot keep up, accumulation of acetaldehyde = unpleasant

common in east asian, uncommon in european

Question 9

Which enzyme activates acetate to acetyl CoA ? Where are the two isoforms if this enzyme distributed?

Answer 9

acetyl CoA synthetase

ACSI is in the cytosolic liver (fatty acid synthesis)

ACSII is in the mitochondria (prepares for TCA)

Question 10

Describe the two components of the cytochrome P450 enzyme. Where is this enzyme located?

Answer 10

an electron donating reductase system that transfers electrons from NADPH (cytochrome P450 reductase) and, cytochrome P450 with binding sites for O2 and ethanol

they are found in the endoplasmic reticulum

Question 11

Does CYP2E1 or ADH have a higher Km for ethanol? How is this relevant to alcohol metabolism in alcoholics?

Answer 11

ADH has a lower Km, which means that CYP2E1 is only metabolizing ethanol under high concentrations (chronic alcoholism)

Question 12

What negative consequences are associated with CYP2E1 induction?

Answer 12

acetylaldehyde is produced faser than it can be degraded (ALDH), leads to an accumulation that enters the blood and can damage other organs

also, cytochrome P450 enzymes are capable of producing free radicals

Question 13

What are the 4 factors that determine the rate and route of ethanol oxidation?

Answer 13

1. gender
2. drinking history
3. genotype
4. quantity

Question 14

ATP yield per molecule of ethanol

ADH route?

CYP2E1 route?

Answer 14

• ADH route
  
  • 13 ATP
• CYP2E1
  
  • 8 ATP

Question 15

What is the effect of the increased NADH/NAD ratio?

Answer 15

• inhibited fatty acid oxidation
• these fatty acids are re-esterfied into triacylglycerols by combining with G-3-P resulting in ethanol-induced hyperlipidemia
• increases availability of G-3-P by promoting its synthesis by glycolysis intermediates
• this leads to fatty liver

Question 16

The high NADH/NAD ratio encourages the production of lactate, ketones and acetate. What is the impact on the blood?

Answer 16

a decrease in blood pH

it also leads to hypoglycemia since glucose precursors are diverted from gluconeogenesis to production of lactate

Question 17

What is the impact of increased blood lactate levels on uric acid?

Answer 17

there is a decrease excretion of uric acid, which leads to the production of gout

this may futher exaggerated by the increased degradation of purines

Question 18

What is the impact on blood glucose levels when alcohol is consumed with a meal?

Answer 18

transient hyperglycemia b/c glycolysis is inhibited by the high NADH/NAD levels

Question 19

Describe acetylaldehyde’s behavior as it is accumulated in the liver?

Answer 19

• highly reactive, binds covlaently with amino groups, sulfhydrul groups, nucleotides, and phospholipids to form “adducts”
• amino acid “adduct” leads to decreased hepatic protein synthesis
• there is an even greater decrease in protein and VLDL secretion
• these proteins accumulate in the liver
• the accumulatin of proteins leads to an increase in water, and a swelling of the liver that disrupts liver architecture

Question 20

Why is it disadvantageous during high a NADH/NAD ratio, that NADH binds directly to gluatathione?

Answer 20

it diminishes glutatione’s ability to protect against H2O2 and prevent lipid peroxidation