Detoxification Mechanisms

Question 1

What are the two steps of hepatic detoxification?

Answer 1

Functionalization (phase I) = use oxygen to form reactive site

Conjugation (phase II) = addition of water-soluble group to reactive site introduced in phase I

Question 2

How does the liver prepare toxic compounds for excretion in the most general sense?

Answer 2

They convert lipophilic compounds to polar, water-soluble derivatives that can be trapped in the urine (can be more toxic, but just easier to excrete)

Does this through oxidation, reduction and conjugation

Question 3

What enzyme adds glucuronic acid?

Answer 3

UDP-glucuronosyltransferases (UGTs)

Question 4

Where is the primary site for ethanol metabolism?

Answer 4

Hepatocytes (liver)

Question 5

What is the most common pathway for alcohol metabolism?

Where does it take place in the cell?

Answer 5

Ethanol (NAD+) —> Acetaldehyde + NADH (alcohol dehydrogenase)
Acetaldehyde (NAD+) —> Acetate + NADH (aldehyde dehydrogenase)
Acetate —> Acetyl CoA (acetyl CoA synthetase/ synthase 2)

In cytosol

Question 6

What minor pathway involving an enzyme that replaces alcohol dehydrogenase and aldehyde dehydrogenase can also deal with ethanol, and where?

When does it become important and what is it’s significance?

Answer 6

In microsomes

Cytochrome P450 does the oxidation instead of AlcD and AldD

Important when ethanol conc. is high

It generates ROS, which can be very damaging to the cell

Question 7

What molecule gives you headache with alcohol?

Answer 7

Acetaldehyde

Question 8

What molecules cause significant metabolic changes with alcohol consumption?

Answer 8

NADH and acetyl CoA, which are over produced in alcohol metabolism

Question 9

What are the metabolic effects of these molecules?

Answer 9

Reduced glycolysis due to lack of NAD+ for glucose oxidation

Lactic acidosis due to lack of NAD+ for lactate dehydrogenase to convert lactate to pyruvate

Reduced gluconeogenesis due to low NAD+ causing inability to convert malate to oxaloacetate

De novo lipogenesis due to high levels of acetyl CoA increasing substrate for FA biosynthesis

Question 10

What causes hyperuricaemia in alcohol metabolism?

Answer 10

Elevated blood levels of uric acid due to formation of acetate which can be converted to uric acid

Uric acid can then crystallise and cause gout