Detoxification By The Liver

Question 1

What is a xenobiotic?

Answer 1

A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism.

Question 2

What is a biotransformation reaction?

Phase I

Phase II

Answer 2

Biotransformation is the process by which a substance changes from one chemical to another (transformed) by a chemical reaction within the body.

Phase I = reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound

Phase II = reactions are conjugation reactions where a molecule normally present in the body is added to the reactive site of the Phase I metabolite . The result is a conjugated metabolite that is more water soluble (hydrophilicity) than the original xenobiotic or Phase I metabolite.

Question 3

Where do biotransformations usually occur?

Answer 3

They occur in the liver in the SER!!!

Question 4

What is a cytochrome P450 enzyme?

Function?

Answer 4

The cytochromes P450 (P450s or CYPs) constitute a large heme enzyme superfamily, members of which catalyse oxidative and other transformation of a wide range of organic substrates, and whose functions are crucial to xenobiotic metabolism.

THEY ARE INVOLVED IN PHASE I REACTIONS

Present in SER

Oxidise substrate

Have a cytochrome reductase subunit which uses NADPH

They generate a free radical component

There activity is induce less by drugs, diet etc

placed into families based on % of a.a that the cytochromes share

Question 5

How can cytochrome P450 enzymes be induced?

By diet example

Answer 5

Activities such as smoking and some drugs can result in decreased concentrations of drugs as they are broken down quicker. Other drugs can cause increased concentrations of medications as they are not broken down.

Grapefruit juice - inhibits cytochrome involved in statin metabolism — increased statin concentration in the blood = toxic

Question 6

Active drugs — new active metabolites

Active drug — inactive metabolite

Prodrug — active agent

Inactive drug to active metabolite

Active drug to reactive intermediate

Answer 6

Pro drug = inactive drug - converted to active in liver

E.g paracetamol — reactive intermediate
Ethanol causes more build up of its toxic intermediate — hepatocyte damage

Question 7

Examples of phase I reactions:

Answer 7

Oxidation : 
Hydroxylation 
Deamination (remove NH) 
Oxygen addition 
Hydrogen removal 

Reduction:
Hydrogen addition
Oxygen removal

Question 8

Example of phase II reaction:

Answer 8

Sulphation

Methylation

Acylation

Phase I ration = expose fucntional group for a phase II reaction

Question 9

Ethanol metabolism doesn’t fit into either Phase

Effect on liver?

Answer 9

• Most of the ethanol in the body is broken down in the liver by an enzyme called alcohol dehydrogenase (ADH), which transforms ethanol into a toxic compound called acetaldehyde.

Acetaldehyde is converted to acetate by oxidation, which is then broken down to CO2 and H2O mostly.

A small amount Is passed out via urine

If the liver can not oxidise acetaldehyde due to being overwhelmed it builds up and leads to alcohol induced hepatitis