Drug Metabolism Flashcards
What is a xenobiotic?
Anything which is foreign to the body
What happens if a xenobiotic undergoes genotoxic activation?
Produces genotoxic carcinogens which bind to DNA and form DNA aducts, damage chromosomes and cause cancer
What happens if a xenobiotic undergoes non-genotoxic activation?
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
What are the 4 phases of gut metabolism?
Distribution
Absorption
Metabolism
Excretion
What is first pass metabolism?
When the drug is absorbed from the gut to the liver for the first time
How can the drug be excreted?
In urine from the bladder
In faeces from the gall bladder
What is drug pharmacokinetics?
What the body does to the drug
What is drug pharmacodynamics?
What the drug does to the body
What is the aim of metabolism?
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
What enzymes are involved in phase 1 metabolism?
P450s
FMO
What enzymes are involved n phase 2 metabolism?
GST
UGT
ST
What happens during phase 1 metabolism?
Creates or exposes an electrophilic/ nucleophilic group through oxidation or reduction
What do electrophilic groups conjugate with in phase 2 metabolism?
GSTs
Where are P450 enzymes located?
In the smooth ER
Where are their high concentrations of FMOs?
In the liver
Where is the subcellular location of FMOs?
In the smooth ER
What are the cofactors of FMOs?
NADPH and molecular oxygen
What happens if there is a mutation in FMOs?
You cannot metabolise trimethylamine and you secrete it as swear
Odorous
What reactions are P450s involved in?
Steroid biosynthesis
Bile acid biosynthesis
Drug/ xenobiotic metabolism
Fatty acid metabolism
Where do P450s receive electrons from?
Through their catalytic cycle from P450 OxidoReductase (POR) using FAD and FMN
What P450s are most commonly involved in drug metabolism?
CYP3A4/5 CYP1A2 CYP2D6 CYP2C19 CYP2C9
What fraction of metabolism is caused by UGTs?
1/3
What is the conjugating moiety of UGTs?
Glucuronic acid
Where is UGT in high concentration?
In the liver, gut and other tissues
Where is the subcellular location of UGTs?
Smooth ER
What is the cofactor of UGT?
UDPGA
What is the conjugating moiety of sulphotransferases?
Sulphate
Where is sulphotransferases found?
Liver, intestine and platelets
Where is the subcellular location of sulphotransferases?
Cytosol
What is the cofactor of sulphotransferases?
PAPS
What superfamily do sulphotransferases belong to?
SULT
What is the conjugating moiety of N-acetyl transferases?
Acetyl group
What is the cofactor for N-acetyl transferases?
Acetyl co-A
Where is N-acetyl transferases found?
Liver, lung and gut
What is the conjugating moiety of methylation?
Methyl group
What is the cofactor for methylation?
S-adenosylmethionine
Where is methylation found?
In many tissues
Why do drug and pro-carcinogens bind to glutathione?
To form less toxic conjugates
What catalyses the conjugation between the drug and glutathione?
GST
What are the subcellular locations of glutathione transferases?
Mitochondria
ER
Nucleus
Cytoplasm
What is phase 0 metabolism?
Transport of the drug into the cell via transporters
What is phase 3 metabolism?
Export of the compounds out of the cell via transporters
Name 2 classes of drug transporters
SLC and ABC
What drugs are used to make another drug more effective via metabolism?
Pump inhibitors
What is the issue with pump inhibitors?
If there is something which needs to be taken up/ removed it cant
Name 2 important nuclear receptors
CAR
PXR
Explain how phenobarbital induces metabolism
binds to CAR -> CAR dimerises with RXR -> fires a series of enzymes which will metabolise phenobarbital
What is the issue with poor metabolisers?
They will experience higher levels of the drug and therefore worse side effects
What is the issue with ultra rapid metabolisers?
They metabolise the drug too fast for it to take effect
How many Ethiopians are ultra rapid metabolisers?
1 in 3 because they have multiple copies of the gene
In terms of metabolism, what is the issue with tamoxifen?
It has to be activated to 4-hydroxy-tamoxifen or endoxifen, however, if you do not have CYP2D6 you cannot do this
In terms of metabolism, what is the issue with using mouse models for pre-clinical trials?
They have a lot more different types of P450 than humans so they metabolise drugs differently - drugs are therefore toxic to humans
