Detoxification of the liver Flashcards
Xenobiotics
Digestion
Have no function
but can be toxic when build up in the liver
ADME
compound journey from absorption to excretion
Phase I
add or exposing functional groups (-OH, -SH, -NH2, -COOH)
a non-synthetic process - not adding any large groups
small increase in hydrophilic molecules
Phase II
x
x
large increase in hydrophilicity
Paracetemol
doesn’t have to undergo phase I, only II
glucuronide (POLAR) is added - to make it water soluble
WHere does detoxification take place?
MOST in the liver
also lungs and mucosa of the gut
In the endoplasmic reticulum, specifically the SER
What is detoxification doing?
inactivation… slide 9
What do cytochrome P450 enzymes all have in common? [6]
Present in smooth ER so ‘microsomal’ enzymes
All oxidise the substrate and reduce oxygen
Cytochrome reductase subunitthat uses NADPH
inducible - activity may be affected by drugs, some dietary components, some environmental toxins eg smoking
Generate a reactive free radical compound
Encoded by a superfamily of more than 50 different genes in humans
Are cytochromes more common in phase I or II
cytochromes predominate phase I metabolism
CYP3A4 - most common - metabolises half of known prescribed medications, many substrates can induce it
fewer genetic variations
CYP2D6 - large number of genetic variations, differences in enzyme action - some people metabolise certain drugs a lot faster
Can one drug only be metabolised by 1 cytochrome?
Multiple cytochromes can work on one drug at any one time
cytochrome P450 reductase
it exists
might provide hydrogen ions for cytochromes
or electrons…
Difference between enzyme induction and inhibition?
induction - speeds up
inhibition - slows down enzyme action
tolernce?
How is grapefruit juice linked to side-effects of statins?
most statins metabolised by CYP3A4
grapefruit juice inhibits metabolism of simvastatin and atorvastatin
increased risk of side effects
