Phase II metabolism

Question 1

SNP

Answer 1

Single nucleotide polymorphism - a single base change

Change AA sequence and can change the amount of transciption occuring

Although in some cases, a change may not have that big of difference as several codons which encode for the same AA

Question 2

Inheritance of Allele

Answer 2

AA - both alleles are active (100% metabolic activity for enzyme activity)

Aa - one active and one is not –> 50% activity

Question 3

Phase II metabolities

Answer 3

Sometime Phase I metabolities may still be lipid soluble and difficult to excrete. In phase ii metabolism, the phase metabolite are conjugated with very polar endogenous molecules. Decreases hydrophobic so thus able to be eliminated.

Question 4

Glucuronidation

Answer 4

conjugation of phase I metabolite to UDP-glucronic acid

• products can be excreted in bile
• nucleophilic substitution reaction
• end up with a sugar molecule which is really polar

Question 5

Example of glucuronidation

Answer 5

Acyl glucuronides
- attachment of sugar to carboxylic acid molecule
NSAID

Question 6

Sulfation

Answer 6

NH2, SO2NH2, OH group by sulfotransferases (SULT) cofactor is PAPS

Drugs which metabolise SULT are cytosolic enzymes

soluble state to be eliminated

Question 7

Acetylation

Answer 7

on NH2 and SO2NH2 and OH by N acetyltransferases (NAT)

Acetyl coenzyme A is a co-factor for NAT
- Transfer of acetly group to each of the precursor making more polar –> readily eliminated

Question 8

Acetylation polymorphism and drug toxicity e.g. Isoniazid

Answer 8

• Individuals who were defective in acetylation experience peripheral neuropathy
• Some individuals who are not able to acetylation and process the drug (shunt this metabolism) and then rely on a minor pathway (oxidation) which causes the build up of toxic chemical, acid.

These individuals are not able to process the drug safely

Question 9

Variation in plasma isoniazid concentrations due to differences in drug acetylation

Answer 9

• Even though the same amount of drug is given to each patient, different in drug acetylation
  Rapid –> able to clear the drug effectively
  Slow–> not clearing as fast

Question 10

NAT2 variants affect acetylation

Answer 10

Those who have active alleles are able to clear more rapidly, unlike those who don’t have to go through alternative pathways

Question 11

Irinotecan

Answer 11

Topoisomerase I inhibitor - the drug prevents the enzyme from unravelling in rapidly dividing cells i.e. cancer where DNA gets tangled.

Question 12

what does topoisomerase do

Answer 12

repairs DNA that gets tangled in rapidly dividing cells

Question 13

Toxicity, biotransformation

Answer 13

activation by hydrolysis of SN-38 (cytotoxic agent which is killing cancer cells)

Question 14

UGT1A1n SN-38

Answer 14

conjugation (no longer toxic + can produce side effects

UGT1A1 catalyses the deactivation of SN-38 to SN-38G

Question 15

DEFECT OF UGT1A1

Answer 15

decreases the rate of UGT1A1 gene transcription –> more of the drug –> toxic –> neutropaenia or diarrhoea