Detoxification By The Liver Flashcards
Where does detoxification take place?
Most (but not all) detoxification takes place in the liver
- inactivation and facilitated elimination of drugs and other xenobiotics
- formation of active metabolites with similar or occasionally enhanced activity
- activation of pro-drugs
- toxification of less toxic xenobiotics
What are cytochrome P450 enzymes?
There are at least 10 main groups of cytochrome-P450 enzymes encoded by a superfamily of at least 55 different genes.
What are some features in common of cytochrome P450 enzymes?
- They are present in the smooth Endoplasmic Reticulum (hence called “microsomal” enzymes)
- They oxidise the substrate and reduce oxygen
hey have a cytochrome reductase subunit which uses NADPH - They are inducible – enzyme activity may be increased by certain drugs, some dietary components, and some environmental toxins eg smoking
- They generate a reactive free radical compound
What is meant by induction of cytochromes?
One drug can induce numerous cytochrome isoenzymes
What is one of the most commonest mechanisms of drug interactions?
Via cytochrome P450
Cytochrome P450 enzymes are inducible, which may accelerate the breakdown of some medications
What can cytochrome P450 be inhibited by?
Cytochrome P450 enzymes can be inhibited by various drugs and foodstuffs (usually takes effect quicker than induction)
It can result in increased blood concentrations of certain medications (less breakdown)
What are some inducers affecting clozapine?
Smoking
(Increased metabolism of drugs)
Barbiturates
Carbamazepine
Primidone
Rifampicin
Cruciferous vegetables, eg cabbage, broccoli
Grilled meat
What agents are known to inhibit clozapine?
Conversely agents including ciprofloxacin
Resulting in increased concentrations of medications such as clozapine
What dietary components may inhibit cytochrome P450?
Grapefruit juice
- A lot of medications are metabolised in Phase I by CYP3A4.
- Most statins are metabolised by CYP3A4.
- By inhibiting metabolism of simvastatin and atorvastatin, grapefruit juice causes increased blood levels with increased risk of side-effects.
What is the inactive metabolite of phenobarbital?
Glucuronides etc
What is the active metabolite of codeine?
Morphite
What is the active metabolite of diazepam?
Oxazepam
What is the reactive intermediate of benzo[a]pyrene?
Reactive metabolite (carcinogenic)
What is the reactive intermediate of paracetamol?
NAPQI (toxic)
What happens during the inactivation of xenobiotic?
An illustration is Phenobarbital which is a barbiturate derivative with both sedative and anti-epileptic activity, metabolised in classic Phase I & Phase II reactions
Phenobarbital is relatively lipophilic; drug distributes into fat tissue
The amount that remains in the plasma is mostly bound to plasma proteins
Only a small fraction of the drug is found freely dissolved in the blood plasma
Elimination of the unmodified drug is thus very slow, and most of the drug is excreted after enzymatic conjugation.
How is codeine metabolised to morphine?
Codeine is a morphine molecule with one hydroxyl group replaced by a methyl group which makes the compound less susceptible to first-pass metabolism (in gut mucosa and liver).
Codeine is active, and is de-methylated in the liver to morphine which is also active.
How is diazepam converted to oxazepam?
Diazepam is demethylated in the liver (a phase-1 reaction) to nordiazepam (an active metabolite).
Nordiazepam is hydroxylated (also a phase-1 reaction) to oxazepam.
Oxazepam is also an active metabolite, and can be prescribed as a shorter-acting sedative.
Oxazepam is metabolised by conjugation (phase-2) and excreted without any phase-1 step.
What are examples of Phase II reactions?
Glycoside conjugation - glucuronidation
Sulphate - sulphation
- Glutathione (GSH)
- Methylation
- Acylation
- Phosphate conjugation
What is responsible for most Phase II reactions?
Transferase enzymes
What are microsomal enzymes?
Location - smooth endoplasmic reticulum
Sites - liver then kidney, lungs, intestinal mucosa
Enzymes – mono-oxygenases, (CYPs,FMOs); UGTs etc
Reactions - majority of drug biotransformation reaction ;
oxidative, reductive & hydrolytic and glucuronidation
Note - they are inducible by drugs, diet etc…
What are non microsomal enzymes?
Location - cytoplasm and mitochondria of hepatocytes, other tissues
Enzymes - protein oxidases, esterases, amidases, conjugases
Reactions - non specific enzymes that catalyze few oxidative,
a number of reductive & hydrolytic reactions and also conjugation reactions other than glucuronidation.
Note - Not inducible but having polymorphism (acetyltransferase & pseudocholinesterase)
How is ethanol metabolised?
Metabolism of ethanol doesn’t fit the category of phase I and Phase II.
Ethanol doesn’t need to be conjugated for excretion.
Only between 2% and 10% is usually excreted in the urine, because it is used in the liver as a dietary fuel.
The major route is via alcohol dehydrogenase (ADH)
What is another route of the metabolism of ethanol?
The other route is via the so-called Microsomal Ethanol Oxidising
System MEOS (predominantly CYP2E1), which also produces acetaldehyde as an intermediate.
The cytochrome P450 isoenzyme CYP2E1 has high affinity for alcohol.
MEOS refers to the combined ethanol-oxidising activity of all CYP450 enzymes.
