Xenobiotics

Question 1

What are Xenobiotics?

Answer 1

They are substances that are foreign to the host. So non-natural molecules such as drugs

Question 2

What processes Xenobiotics?

Answer 2

Enzymes that evolved to cope with natural compounds

Question 3

What are the properties of Xenobiotics and the advantages of them?

Answer 3

Non-polar

Lipophilic - helps them to get across

Question 4

How can you change the rate of metabolism?

Answer 4

By reacting with other substances

Question 5

Is metabolism the same for everyone?

Answer 5

No, everyone has their own unique metabolic profile

Question 6

Name some ways drugs Xenobiotics can be absorbed?

Answer 6

Active absorption of molecules by transport proteins

Absorption by dissolution in fats (lipophilicity)

Question 7

What factors increase Absorption?

Answer 7

A high concentration of Xenobiotics in the circulation, than in the site of action.

Slow movement within the GIT

Taking the drug with food will favour absorption. As the movement of the food, through the small intestine, will be slow.

Question 8

Can charged Xenobiotics such as salt pass through the membrane easily?

Answer 8

No, because membrane proteins have charged residues designed to repel xenobiotics

Question 9

Where are weak acids and weak bases absorbed in?

Answer 9

Weak acids are absorbed in the stomach

Weak bases are absorbed in the SI

Question 10

Factors which affect Distribution?

Answer 10

• Log P
• Blood flow through the tissue (perfusion of the tissue)
• The mass of the tissue
• Plasma/tissue concentration gradient

Question 11

What does the Tubular section provide?

Answer 11

An active carrier process for cations and anions

Question 12

Explain the process of the Entero-hepatic shunt?

Answer 12

Glucuronic acid conjugates can be excreted in the bile

The B-glucuronidase in the GIT will hydrolyse the carbohydrate conjugate

Active xenobiotic may then be reabsorbed

Question 13

What is the purpose of phase 1 metabolism?

Answer 13

To create functional groups that place Xenobiotics in a correct chemical state to be acted upon at phase 2

Question 14

What are the properties of CYP(450)

Answer 14

Large
Membrane-bound
Contain a heme residue (iron, Fe2+/3+)

Question 15

What is the equation for the oxidation of a substrate?

Mono-oxygenase biotransformation reactions

Answer 15

NADPH + H+ + O2 + SubstrateH

—->

NADP+ +H20 + SubstrateOH

Question 16

Where are CYPs found?

Answer 16

Endoplasmic reticulum (ER) of Hepatocytes

Small amounts in GIT

Kidney

Question 17

What do CYP family and CYP subfmaily have?

Answer 17

CYP family has 40% sequence homology

CYP subfamily has 55% sequence homology

Question 18

Explain the CYP 450 cycle?

Answer 18

The drug associates with the enzyme and causes it to be reduced from Fe3+ to F2+ (e- gained).

Oxygen associates with the complex and another electron comes in. Then the oxygen becomes activated to give a poroxy substituent (OOH)

It is then activated further to give a very high active species, where the iron is activated from 2+ to 3+.

The oxygen then attacks the drug, resulting in the drug and a hydroxyl group added onto it.

Question 19

Name some CYP 450 Oxidations and what they do?

Answer 19

Aromatic/Aliphatic hydroxylation (adds OH)

Esther hydrolysis (removes ester, OOEt)

N-dealkylation (replaces a hydrogen with an alkyl group)

Oxidative deamination (removes an ammonia group and adds a ketone group)

Question 20

What is used in phase 2 metabolism?

Answer 20

A high-energy co-factor that is involved in the conjugation

Question 21

What is the result of phase 2 metabolism?

Answer 21

A water-soluble product which can be readily excreted

Question 22

What are the main Phase 2 pathways?

Answer 22

The conjugation of a-D-glucuronic acid with a carbohydrate (forms glyosidic bond)

Question 23

What does the conjugation of a-D-glucuronic acid require?

Answer 23

UDP-glucuronic acid intermediate

and

UDP-glucuronosyltransferases (UGTs, found within cytosol)

Question 24

What is needed for Sulfation?

Answer 24

PAPS - 3’-Phosphoadenosine-5’-phosphosulfate intermediate

and

Sulfotransferases (SULTs, usually in the cytosol)

Question 25

When is Glucuronidation and Sulfation used?

Answer 25

Glucuronidation predominates at high substrate concentration

Sulfation predominates at low substrate concentration

Because there is less PAPS in cell cytosol than UDPGA

Question 26

Summarise Glutathione conjugation?

Answer 26

Because Glutathione is a nucleophile, the substrates are highly electrophilic compounds.

Glutathione-S-transferase (GSTs) are used; normally found in cytosol

The conjugates can be attacked by g-glutamyltranspeptidase
and a peptidase to yield the cysteine conjugate.

Conjugates are excreted in the bile or via kidney.