Drug Metabolism

Question 1

What is a xenobiotic?

Answer 1

Anything which is foreign to the body

Question 2

What happens if a xenobiotic undergoes genotoxic activation?

Answer 2

Produces genotoxic carcinogens which bind to DNA and form DNA aducts, damage chromosomes and cause cancer

Question 3

What happens if a xenobiotic undergoes non-genotoxic activation?

Answer 3

It does not directly bind to DNA
Can increase ROS, inflammation, epigenetic silencing, receptor activation and immunosuppression
The change in cellular processes can alter DNA and cause cancer

Question 4

What are the 4 phases of gut metabolism?

Answer 4

Distribution
Absorption
Metabolism
Excretion

Question 5

What is first pass metabolism?

Answer 5

When the drug is absorbed from the gut to the liver for the first time

Question 6

How can the drug be excreted?

Answer 6

In urine from the bladder

In faeces from the gall bladder

Question 7

What is drug pharmacokinetics?

Answer 7

What the body does to the drug

Question 8

What is drug pharmacodynamics?

Answer 8

What the drug does to the body

Question 9

What is the aim of metabolism?

Answer 9

To get a compound which is normally not water soluble and not easily excreted to make it more water soluble so it can be excreted

Question 10

What enzymes are involved in phase 1 metabolism?

Answer 10

P450s

FMO

Question 11

What enzymes are involved n phase 2 metabolism?

Answer 11

GST
UGT
ST

Question 12

What happens during phase 1 metabolism?

Answer 12

Creates or exposes an electrophilic/ nucleophilic group through oxidation or reduction

Question 13

What do electrophilic groups conjugate with in phase 2 metabolism?

Answer 13

GSTs

Question 14

Where are P450 enzymes located?

Answer 14

In the smooth ER

Question 15

Where are their high concentrations of FMOs?

Answer 15

In the liver

Question 16

Where is the subcellular location of FMOs?

Answer 16

In the smooth ER

Question 17

What are the cofactors of FMOs?

Answer 17

NADPH and molecular oxygen

Question 18

What happens if there is a mutation in FMOs?

Answer 18

You cannot metabolise trimethylamine and you secrete it as swear
Odorous

Question 19

What reactions are P450s involved in?

Answer 19

Steroid biosynthesis
Bile acid biosynthesis
Drug/ xenobiotic metabolism
Fatty acid metabolism

Question 20

Where do P450s receive electrons from?

Answer 20

Through their catalytic cycle from P450 OxidoReductase (POR) using FAD and FMN

Question 21

What P450s are most commonly involved in drug metabolism?

Answer 21

CYP3A4/5
CYP1A2
CYP2D6
CYP2C19 
CYP2C9

Question 22

What fraction of metabolism is caused by UGTs?

Answer 22

1/3

Question 23

What is the conjugating moiety of UGTs?

Answer 23

Glucuronic acid

Question 24

Where is UGT in high concentration?

Answer 24

In the liver, gut and other tissues

Question 25

Where is the subcellular location of UGTs?

Answer 25

Smooth ER

Question 26

What is the cofactor of UGT?

Answer 26

UDPGA

Question 27

What is the conjugating moiety of sulphotransferases?

Answer 27

Sulphate

Question 28

Where is sulphotransferases found?

Answer 28

Liver, intestine and platelets

Question 29

Where is the subcellular location of sulphotransferases?

Answer 29

Cytosol

Question 30

What is the cofactor of sulphotransferases?

Answer 30

PAPS

Question 31

What superfamily do sulphotransferases belong to?

Answer 31

SULT

Question 32

What is the conjugating moiety of N-acetyl transferases?

Answer 32

Acetyl group

Question 33

What is the cofactor for N-acetyl transferases?

Answer 33

Acetyl co-A

Question 34

Where is N-acetyl transferases found?

Answer 34

Liver, lung and gut

Question 35

What is the conjugating moiety of methylation?

Answer 35

Methyl group

Question 36

What is the cofactor for methylation?

Answer 36

S-adenosylmethionine

Question 37

Where is methylation found?

Answer 37

In many tissues

Question 38

Why do drug and pro-carcinogens bind to glutathione?

Answer 38

To form less toxic conjugates

Question 39

What catalyses the conjugation between the drug and glutathione?

Answer 39

GST

Question 40

What are the subcellular locations of glutathione transferases?

Answer 40

Mitochondria ER Nucleus Cytoplasm

Question 41

What is phase 0 metabolism?

Answer 41

Transport of the drug into the cell via transporters

Question 42

What is phase 3 metabolism?

Answer 42

Export of the compounds out of the cell via transporters

Question 43

Name 2 classes of drug transporters

Answer 43

SLC and ABC

Question 44

What drugs are used to make another drug more effective via metabolism?

Answer 44

Pump inhibitors

Question 45

What is the issue with pump inhibitors?

Answer 45

If there is something which needs to be taken up/ removed it cant

Question 46

Name 2 important nuclear receptors

Answer 46

CAR | PXR

Question 47

Explain how phenobarbital induces metabolism

Answer 47

binds to CAR -> CAR dimerises with RXR -> fires a series of enzymes which will metabolise phenobarbital

Question 48

What is the issue with poor metabolisers?

Answer 48

They will experience higher levels of the drug and therefore worse side effects

Question 49

What is the issue with ultra rapid metabolisers?

Answer 49

They metabolise the drug too fast for it to take effect

Question 50

How many Ethiopians are ultra rapid metabolisers?

Answer 50

1 in 3 because they have multiple copies of the gene

Question 51

In terms of metabolism, what is the issue with tamoxifen?

Answer 51

It has to be activated to 4-hydroxy-tamoxifen or endoxifen, however, if you do not have CYP2D6 you cannot do this

Question 52

In terms of metabolism, what is the issue with using mouse models for pre-clinical trials?

Answer 52

They have a lot more different types of P450 than humans so they metabolise drugs differently - drugs are therefore toxic to humans