1. CYTOCHROME P-450
IN
THERAPEUTICS
Dr. DIVYA G KRISHNAN
CALICUT MEDICAL COLLEGE
2. CASE HISTORY………………………….
A 74 year old woman on warfarin & metoprolol for AF brought
with symptoms of depression.The treating doctor prescribed
Fluoxetine.
3 days later patient brought to casualty dizzy & complained of
difficulty in urinating.Cathetrisation of bladder yielded 2litres
of dark urine.Her PT/INR was 4.
On discussion with a colleague,the treating doctor learned that
Fluoxetine inhibits CYTOCHROME P 450 enzymes
responsible for the metabolism of patient’s other medications.
4. INTRODUCTION
Humans constantly exposed to xenobiotics(usually non polar)
that can cause harm if not eliminated.
Biotransformation renders non polar compounds polar and
helps in their elimination.
Biotransformation occurs in 2phases(phase1 &phase 2)
Cytochrome p-450 is a superfamily of enzymes that
catalyse most of the oxidation reactions of phase 1.
5. HISTORY…………………………………….
1955 : First evidence of, presence of an enzyme in the liver
endoplasmic reticulum, capable of oxidising xenobiotics.
1964 : Enzyme demonstrated to be a hemoprotein and was
named CYTOCHROME P 45O
1985 : Full structure of P 450 cam from bacteria
Pseudomonas putida obtained.Now crystal structures of
most enzymes available.
6. HISTORY CONTINUED…………………….
Origin of the name CYTOCHROME P 450
Cytochrome=cellular pigment P 450 denotes the
Being a hemoprotein capable of absorption peak at
oxidation reactions,it came to be 450nm(SORET PEAK)
called a cytochrome.
CYTOCHROME P 450
CYP 450
12. OTHER OXIDATION REACTIONS……………..
N Dealkylation
Eg: morphine to normorphine
O Dealkylation
Eg: phenacetin to paracetamol
S Dealkylation
Eg: 6 methylthiopurine to 6 mercaptopurine
N Oxidation
Eg: CPM , Dapsone
S Oxidation
Eg: CPZ to CPZ sulfoxide
Deamination
Eg:amphetamine to phenylacetone
Desulfurisation
Eg:parathion to paraoxon
14. CYPS IMPORTANT IN MAN……………..
50 cyps grouped into 17 families and 30 sub families
Cyps belonginging to families 1 to 3 involved in drug
metabolism.
15. PROPERTIES OF CYP 450ENZYMES……………………
1.CYPs involved in xenobiotic metabolism as well as
metabolism of endogenous substances.
Xenobiotic metabolising CYPs Endogenous substances
metabolising CYPs
Substrate overlapping Specific substrate specificities
Can metabolise multiple
substrates at a time
Metabolise only a
single,specific substrate at a
time.
Slower rate of metabolism Faster rate of metabolism
16. PROPERTIES CONTD…………….
2. INDUCTION
Drugs on continuous administration induce CYPs by
increased synthesis or decreased degradation
MECHANISMS OF INCREASED SYNTHESIS
-transcription of genes coding for CYP enzymes
-drugs act as ligands for receptors involved in transcription
of genes
Cytosolic receptor(AHR)
Receptors------
Nuclear receptors(PXR,CAR,PPAR)
17. INDUCTION BY AHR
Polycyclic hydrocarbons,omeprazole etc bind to AHR
Ligand receptor complex translocated into nucleus where
it forms a dimer with nuclear protein Arnt.
Dimer results in transcription of genes coding for
CYP1A1,CYP1A2,CYP1B1.
The 3 CYPs are involved in conversion of procarcinogens to
carcinogens.Hence their induction leads to increased risk of
carcinogenicity.
18. INDUCTION BY NUCLEAR RECEPTORS
PXR : CYP3A4 induction by ligands like
rifampicin,atorvastatin,St John’s wort
CAR : CYP2B6,CYP2C9,CYP3A4 induction by
phenobarbitone.
PPARα : CYP4A induction by fibrate group of drugs.
19. OUTCOMES OF ENZYME INDUCTION
Decreased intensity of action of drugs that are metabolised to
inactive metabolites.
eg:-failure of OCP by rifampicin
-higher doses of warfarin needed if administered with
barbiturates
Increased intensity of action of drugs activated by
metabolism-toxicity
eg:-paracetamol to N-acetyl benzoiminoquinone in
alcoholics due to induction of CYP2E1.
Carcinogenesis due to induction of CYP2E1,CYP1A1/2
20. Pharmacokinetic tolerance
Increased metabolism of endogenous substances
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3.ENZYME INHIBITION
Occurs by either of the following mechanisms:-
-competitive inhibition(reversible)
-irreversible inactivation of enzyme
Outcomes of enzyme inhibition
-augmentation of plasma drug levels of drug whose metabolism
is inhibited--toxic effects
Eg:- terfenadine with CYP3A4 inhibitor
ketoconazole/erythromycin fatal arrythmias.
- cisapride with CYP3A4 inhibitors cardiotoxicity
21. 4.GENETIC POLYMORPHISM
CYP2D6 Polymorphisms
slow metabolisers ultrarapid metabolisers
(Debrisoquin sparteine
Oxidation type polymorphism)
CYP2C19 in mephenytoin metabolism
polymorphic form produces metabolism of both (S) & (R)
Mephenytoin to nirvanol-profound sedation & ataxia
CYP2A6 polymorphism
Individuals with null alleles are proteceted against smoking
22. CLINICAL RELEVANCE OF CYPS
Drug interactions can be explained by induction & inhibition.
Knowledge about CYPs helps in :-
-avoiding potentially dangerous interactions
-dosage adjustments when certain drugs are co-administered
-dose adjustments in elderly,disease states,alcoholics
Explains the risk of carcinogenicity with smoking,alcohol
consumption of charcoal broiled meat etc
Genetic polymorphisms help in understanding interindividual
variations and atypical responses
-Genotyping of P 450 profiles to detect polymorphisms
may help in individualisation of therapy
24. SUMMARY
CYPs involved in phase 1 oxidation of 50% of drugs
Hemoproteins located in liver ER(microsomal
enzymes)/mitochondria
Broad substrate specificity
Many are inducible,resulting in one cause of drug
interaction
Many are inhibited by drugs/metabolites,another cause
od drug interaction
In some cases the products of metabolism are
carcinogenic
Some exhibit genetic polymorphism.Genotyping will help
in individualisation of therapy