Flashcards in LIVER - DETOXIFICATION Deck (42)
what is the function of detoxification of drugs?
to make it more polar and therefore more soluble
this means it can be excreted in urine
what is the method of detoxification in the liver?
via phase I and phase II reactions
what are phase I reactions?
- the addition/exposure of a functional group
- it is non-synthetic
what is the effect of phase I reactions on hydrophilicity?
it produces only a small increase of hydrophilicity
what types of reactions are involved in phase 1 detoxification?
give examples of oxidation reactions involved in phase 1 reactions?
hydroxylation (addition of -OH group)
N- and O- dealkylation (removal of -CH side chains)
deamination (removal of NH side chain)
give examples of reduction reactions involved in phase 1 reactions?
hydrogenation (unsaturated -> saturated)
give examples of hydrolysis reactions involved in phase 1 reactions?
splitting amide and ester bonds
what are phase II reactions?
conjugation to produce hydrophilic metabolites
what is the effect of phase II reactions on hydrophilicity?
produce a large increase in hydrophilicity
give examples of phase II reactions
what are xenobiotics?
foreign substances that have no nutritional value so need to be excreted
how are xenobiotics ingested?
what are the dangers of xenobiotics?
they damage proteins, lipids and can bind to DNA (are carcinogens)
they react with O2 and release free radicals
where are microsomal enzymes found?
in smooth ER of liver, kidneys and intestinal mucosa
give examples of microsomal enzymes?
what reactions are microsomal enzymes involved in?
the majority of drug biotransformation reactions
are microsomal enzymes inducible?
yes - by drugs and diet
where are non-microsomal enzymes found?
in cytoplasm and mitochondria of hepatocytes
give examples of non-microsomal enzymes
protein oxidases, esterases etc
what reactions are non-microsomal enzymes involved in?
non-specific enzymes for conjugation
are non-microsomal enzymes inducible?
what are cytochrome P450?
there are at least 10 main groups
they are encoded by a superfamily of 60 different genes
where are CYP450 found?
in smooth ER
what reactions are CYP450 involved in?
phase I biotransformation reactions
oxidise substrates and reduce oxygen
they are inducible
what are the properties of CYP450?
have cytochrome reductase subunit - uses NADPH
they generate a free radical
they have affinity for CO and O2
which is the most common cytochrome?
CYP3A4 - it is responsible for 2/3 of all drug reactions
how is cytochrome P450 induced?
- molecule binds to intracellular receptor within cytoplasm
- the molecule receptor complex migrates to nucleus
- this increases transcription of mRNA for cytochrome P450
- this increases the effect of the cytochrome
what is the mechanism of action of cytochrome P450?
- CYPs contain haem component which is capable of oxidising molecules (-OH addition) by becoming reduced themselves
- the reductases use NADPH to become active
- the reductases reduce CYPs allowing oxidation of the foreign molecule
- the reaction forms water and has an intermediate of a haem free radical