7. Cytochrome P450 Flashcards
Where are the cytochrome p450 enzymes found?
What category of reactions are they responsible for?
In the lipid belayer of the smooth ER of the liver (also found in kidneys, brain, adrenals and gut in much smaller concentrations).
Phase 1 reactions: changing lipophilic to hydrophilic. Helps absorption in the gut wall and excretion in the kidney.
What kind of enzymes are the P450 enzymes?
Mono-oxygenase
Why are the cytochrome enzymes named such?
Cytochrome means cell colour.
They contain iron and when reduced they combine with CO to absorb light at a wavelength of 450nm. They give the liver its red colour.
How are cytochrome enzymes named?
CYP2D6
CYP = cytochrome P4t0 (root)
2 = genetic family (18)
D = genetic subtype (44)
6 = specific gene
In the liver, what cytochrome enzymes are responsible for changing cholesterol to bile acids?
7A and 27A
In the liver, what cytochrome enzymes are responsible for endogenous steroid production?
11, 17, 19 and 21
In the kidneys, what do the cytochrome enzymes do?
What is EET, what does it do and what cytochrome enzyme metabolises this?
HETE?
Produce arachidonic acid metabolites.
Epoxyeicosatrienoic acid - renal vasodilation and glomerular permeability. = 2C
Hydroxyeicosatrienoic acid = renal vasoconstriction and inhibits Na reabsorption via Na/K pump. = 4A
In the brain, what do the cytochrome enzymes do?
Involved in production of steroid hormones and prostaglandin metabolites for:
Regulation of H/P peptide hormones
Regulation of tone by arachidonic acid metabolites
Reg of progesterone and corticosteroids influencing mood via gaba receptors
What are iso forms?
Versions of proteins with small differences to each other
What are the most important cytochrome families for drug metabolism?
What does each family contain and what can effect these?
Cyp1, 2 and 3
Several different isoforms.
Each encoded by a single gene, so genetic variability can effect this.
Also enzyme inducers/inhibitors
What are the most important isoforms in the CYP1 family?
What do they do and what are their inducers?
A1: metabolise polycyclic aromatic hydrocarbons e.g. theophylline, propranolol and caffeine
Induced by: smoking, charbroiled meat, phenobarbital and phenytoin.
A2: inhibited by cipro and fluvoxamine
Can produce toxic levels of theophylline
What are the CYP2 family enzymes that are most important in drug variation due to genetic differences?
What do they metabolise and what are there inducers/inhibitors?
2C9: absent in most afrocarribeans and 1% white.
Metabolise: pro-drug losartan, s-warfarin, NSAIDs and phenytoin
Inhibitors: fluconazole (strongly) and amiodarone (mod)
2C19: absent in 30% Asians and 5% whites.
Metabolise: diazepam, phenytoin and omeprazole
Inhibited by: PPI’s (strongly), ketoconazole and cimetidine
2D6: is responsible for metabolism of 25% of drugs. Absent in 10% white and 3% non. 30% East Africans have multiple copies and are extensive metabolisers.
Metabolise: codeine, tramadol, beta blockers, tricyclic and SSRI, anti-arrhythmic and ondansetron.
Inhibited by: fluoxetine, paroxetine and quinidine (strongly), amiodarone (mod) and cimetidine (mod)
2E1: metabolises volatiles, ethanol and paracetamol
Induce: isoniazid and chronic alcohol
Inhibited: disulfaram and acute alcohol consumption.
Hoe many isoforms does the CYP3 family have?
What is the most important?
What does it do?
Inducers/inhibitors?
4.
3A: mostly in the GI tract. Metabolises, CCBs, benzos, antihistamines, lidocaine and fent/alfi
Inducers: rifampicin, glucocorticoids, ST johns wart, phenobarbital, carbemazepine, phenytoin
Inhibit: cimetidine, erythromycin, amiodarone, grapefruit and ketoconazole
What are the most important CYP’s that are liable to polymorphisms?
Who is affected, how and what happens?
2D6:
10% of white people. PM: Codiene and tramadol ineffective
UM: 30% Ethiopians UM’s: side effects of codeine and tramadol
2C9 and 2C19.
20-30% Asians are poor metabolisers, with reduced clearance of diazepam, phenytoin and omeprazole (higher H.pylori cure rate)
What three groups can patients with altered CYP polymorphisms be categorised into?
Poor metabolisers
Rapid metabolisers
Ultra-rapid
