Metabolism Flashcards
5 Major Isoforms of CYP
CYP1A2 CYP2C9 CYP2C19 CYP2D6** CYP3A4*****
*****Most important: About 50% of drugs
**2nd most important
Co-Factors of Cytochrome P450
NADPH*
flavoprotein
O2*
2H+
Major chemical/functional group transformations by CYP (7 rxns)
- aliphatic and aromatic hydroxylation
- alkene and aromatic epoxidation
- N-, O-, S-dealkylation
- N-oxidation; N-hydroxylation
- oxidative deamination and desulfuration
- S-oxidation
- oxidative dehalogenation
Other Phase 1 enzymes (5)
- Flavin adenine dinucleotide (FAD) monoxygenase
- monoamine and diamine oxidase
- alcohol dehydrogenase
- acetaldehyde DH
- xanthine oxidase
5 Phase 2 Reactions
Time 2 say “Good Night SAM”
Glucuronidation Sulfation Mercapturic acid formation N-, O-, S-methylation Acetylation
Glucuronidation:
UGTs: uriidine diphosphate-glucuronyl transferase
19 isoforms; mainly found in liver but also intestine, kidney, skin
Adds glucuronic acid to acceptor molecules (hydroxyls,carboxylic acids, thiols, amines)
Endogenous substrates include bilirubin, bile acids, steroid hormones
Result: Increased polarity –>increased excretion
Sulfation
sulfotransferases
11 isoforms; found in liver, intestine, lung, adrenal glands
Attaches sulfate groups to hydroxyl groups
3’-phosphoadenosine-5’-phosphosulfate (PAPS) is donor
Result: Increased MW and polarity; now above receptor threshold and can be excreted
Mercapturic acid formation
glutathione-S-transferase
(GST)
Found in liver, kidney, lung, intestine
Adds glutathione (Gly-Cys-Glu) to acceptor molecules
Followed by hydrolysis of the glutamate and glycine, then acetylation of the cysteine
Result: chemistry has changed majorly and so
now it’s super unlikely to bind to its
receptor site
N-, O-, S-methylation
methyl transferases
Phenylethanolamine-N-methyltransferase, histamine-Nmethyltransferase,
indolethylamine-N-methyltransferase,
catechol-O-methyl transferase, thiol-S-methyltransferases
Tissue distribution: liver, kidney, lung, brain
Adds methyl group from S-adenosyl methionine to acceptor molecules
Result: ?
Acetylation
Arylamine N-acetyltransferase
2 isoforms are important in xenobiotic metabolism
Catalyzes the transfer of an acetyl group from acetyl CoA tovarious amine and hydrazine acceptor molecules
CYP Induction
Also UGT and GST can be induced
Increases Phase I metabolism (functionalization)
Polycyclic aromatic hydrocarbons (found in combustion products: smoke, BBQ, etc.)
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
Glucocorticoids (dexamethasone, prednisone, triamcinolone)
*****Peroxisome proliferator activated receptor α agonists (clofibrate, fenofibrate):lowers TGs w/known side effect of CYP induction
Rifampin-antibiotic
St. John’s Wort: potent CYP3A4 inducer
HIV drugs (efavirenz, nevirapine, ritonavir)
UGT Inducers
Phenobarbital
3-methylcholanthrene (antiseizure)
Carbamazepine (antiseizure)
Nicotine
GST Inducers
Phenobarbital
3-methylcholanthrene
Allyl isothiocyanate (wasabi, horseradish)
Carvone (spices)
Enzyme Inhibition : Types
Cofactor depletion
Reversible competitive inhibition:
Covalent inhibition
Pseudoirreversible inhibition:
Enzyme Inhibition : Covalent Inhibition
reactive intermediates covalently modify and inactivate enzymes Disulfiram: inhibits aldehyde dehydrogenase Polyhalogenated compounds Olefinic and acetylenic drugs
Enzyme Inhibition : Reversible Competitive Inhibition
substrates for metabolic enzymes can compete for binding sites with other drugs and inhibit their metabolism
Examples:
Antibiotics (clarithromycin, erythromycin)
Gemfibrozil
Azole-class antifungals (itraconazole, ketoconazole,
posaconazole, voriconazole)
HIV protease inhibitors (indinavir, ritonavir, saquinavir)
1st generation H2 antagonists (cimetidine)
Grapefruit juice
Enzyme Inhibition : Pseudoirreversible
metabolism results in
intermediates which slowly dissociate
Therapeutic examples of enzyme inhibitors
MAO inhibitors
Example: pargyline ↑ concentration of biogenic monoamines (serotonin, norepinephrine, dopamine)
Aromatic L-amino acid decarboxylase inhibitors
Example: carbidopa longer half-life of levodopa ↑ plasma concentration and CNS availability
can decrease the dose of levodopa required to treat Parkinson’s disease
Xanthine oxidase inhibitors
Example: allopurinol ↓ uric acid biosynthesis ↓ gouty deposits
Peptidase inhibitors
Example: cilastatin inhibits renal dehydropeptidase-I, which is responsible for b-lactam inactivation
↑ therapeutic activity of blactamantibiotics (penicillin)
Genetic Variations in CYP
CYP polymorphisms: CYP2C9, CYP2C19, CYP2D6
Drugs affected: warfarin, omeprazole, codeine,
dextromethorphan, most SSRIs, many antipsychotic agents, beta-blockers
CYP2D6 mutations are the most common CYP
polymorphism
Ultra-rapid metabolizers vs. Poor Metabolizers
Other Genetic issues affecting drug metabolism
1.. N-acetyl transferase activity leads to Isoniazid and procainamide inactivation
Fast acetylators-lower serum [drug] and smaller T1/2
-slow acetylators
- COMT deficiency
Decreased isoproterenol metabolism - Thiopurine-S-methyltransferase deficiency
Azathioprine, 6-mercaptopurine toxicity - Butyrylcholinesterase (pseudocholinesterase) activity
Succinylcholine sensitivity
Succinylcholine resistance
