Ethanol Metabolism

Question 1

What variables are there in the elimination rate of ethanol?

Answer 1

Both genetic and environmental factors, including: sex, age, food, biological rhythms, exercise, drugs, quantity consumed, and drinking history

Based off of these variables there can be a 3-4 fold difference in ethanol elimination rate

Question 2

Ethanol basic chemical properties

Answer 2

Small and water-soluble alcohol CH3CH2OH

Question 3

How does ethanol cause disorienting effects?

Answer 3

It alters the fluidity of neuronal lipids, changing their responses to neurotransmitters

Question 4

What happens to ethanol after it is absorbed?

Answer 4

Portal circulation from the gut first passes through the liver, thus the majority of ingested ethanol (85-98%) is metabolized by hepatocytes, making the liver the major site of tissue injury caused by excessive drinking

Question 5

What is the main ethanol metabolism pathway?

Answer 5

Occurs in the cytoplasm of hepatocytes

Metabolizes ~80-90% of ingested ethanol in a moderate drinker

Initiated by enzyme alcohol dehydrogenase (ADH1) which has a low KM (high affinity)

Question 6

What is the secondary ethanol metabolsim pathway?

Answer 6

Microsomal Ethanol Oxidation System

Smooth ER of hepatocytes

Metabolizes ~10-20% ingested ethanol in a moderate drinker

CYP2E1 enzyme (cytochrom P450) irreversibly oxidizes ethanol to acetaldehyde (higher Km, lower affinity, used more when more ethanol consumed)

Inducible 5 to 10 fold increase in CYP2E1 in chronic consumption –> Leads to faster acetaldehyde production to the point where the next enzyme can’t keep up, causing buildup of acetaldehyde which is toxic

Question 7

What component of ethanol metabolism is toxic and how does it accumulate?

Answer 7

Acetaldehyde, which accumulated when it can’t be converted to Acetate quickly enough due to excess alcohol consumption

Question 8

Ethanol Metabolism Pathway (Chart)

Answer 8

Question 9

In addition to the cytoplasmic (ADH) pathway of alchol metabolsim, what other systems converts ethanol into acetaldehyde?

Answer 9

Microsomal ethanol oxidation system

Question 10

Microsomal ethanol oxidation system (process)

Answer 10

Cytochrome P450 reductase passes electrons to Cytochrome P450 causing Fe3+ –> Fe2+ in Cytochrome P450

Can then convert ethanol + O2 –> acetaldehyde + H2O

May lead to reactive oxygen species (ROS) d/t transfer of single electrons

Question 11

What might the buildup of reactive oxygen species lead to?

Answer 11

Hepatic injury + Cirrhosis + DNA damage

Question 12

What does acetaldehyde do if it’s not converted to acetate in time and starts to accumulate?

Answer 12

Acetaldehyde binds to cellular macromolecules (such as proteins, lipids, DNA, and RNA) forming an inactive addition products

Question 13

What symptoms result from acetaldehyde accumulation?

Answer 13

Nausea

Vomiting

Flushing

Sweating

Dizziness

Question 14

What does the enzyme alcohol dehydrogenase do?

Answer 14

Converts ethanol to acetaldehyde in the cytoplasm (primary pathway of ethanol metabolism)

Has a low Km –> high affinity

Question 15

What does the enzyme CYP2E do?

Answer 15

Irreversibly converts ethanol to acetaldehyde in the Microsomal Ethanol Oxidation System (MEOS/secondary ethanol metabolism pathway)

Higher Km = Lower affinity

Question 16

What does the enzyme acetaldehyde dehydrogenase (ALDH2) do?

Answer 16

Converts Acetaldehyde (which is toxic) to Acetate

Low Km = High affinity

Question 17

What is ALDH2*2?

Answer 17

An allelic variant of ALDH2 (the enzyme that converts toxic Acetaldehyde to Acetate)

Changes the Km from 0.2 to 64! Much lower affinity! Causing the accumulation of acetaldehyde in the blood.

Common in Asian populations and is associated with a higher incidence of certain cancers

Question 18

What is Disulfiram?

Answer 18

An acetaldehyde dehydrogenase inhibitor that can help alcoholics refrain from alcohol intake because it leads to elevated levels of acetaldehyde (which is toxic and causes unpleasant symptoms)

Can be dangerous for those who still continue to consume alcohol

Question 19

How does ethanol consumption influence the NADH to NAD+ ratio?

Answer 19

Oxidation of each molecule of ethanol to acetate by ADH produces 2 NADH and consumed 2 NAD+

Increases NADH to NAD+ ratio

Question 20

With relation to the liver, what does an increased NADH to NAD+ ratio result in?

Answer 20

This increased ratio inhibits the B-oxidation of fatty acids, causing fatty acid accumulation in the liver

Also increases production of glycerol 3-phosphate and stimulates triacylglycerol synthesis –> which are incorporated into very-low-density lipoproteins (VLDLs) and accumulate in the liver and enter the blood stream causing ethanol-induced hyperlipidemia and increased chances of developing fatty liver

Question 21

With relation to the TCA cycle, what does an increased NADH to NAD+ ratio result in?

Answer 21

Also shifts oxaloacetate in the TCA cycle to malate, leaving [oxaloacetate] too low for citrate synthase to make citrate, inhibiting the TCA cycle, resulting in excess acetyl CoA being converted into ketone bodies causing alcoholic ketoacidosis

Question 22

With relation to the conversion of pyruvate to lactate, what does a high NADH to NAD+ ratio result in?

Answer 22

Increases conversion of Pyruvate to Lactate by Lactate Dehydrogenase

Causes lactic acidemia or hypoglycemia in a fasting person dependant on gluconeogenesis

Elevated blood lactate may also decrease excretion of uric acid by the kidneys; thus, those with gout are advised not to drink excessive amounts. Increased degradation of purines may also contribute to hyperuricemia and gout