Cytochrome P-450 enzymes are a superfamily of heme-containing enzymes located in the liver endoplasmic reticulum that catalyze the oxidation of many drugs and xenobiotics. A case study described a patient who developed toxicity when fluoxetine was prescribed, as it inhibited the cytochrome P-450 enzymes responsible for metabolizing the patient's other medications. Cytochrome P-450 enzymes can be induced or inhibited by other drugs, causing interactions, and some exhibit genetic polymorphisms, demonstrating the clinical importance of considering these enzymes in drug therapy.

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.

3. CONTENTS……………………
 Introduction
 History
 Location
 Structure
 Mechanism of action
 Nomenclature
 Properties
 Clinical relevance
 Summary

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

7. LOCATION……………………………
HEPATOCYTE

8. LOCATION……………………….

9. STRUCTURE……………………………

10. MECHANISM OF ACTION………………
 Microsomal oxidations require:-
CYP 450
CYP 450 REDUCTASE
NADPH
OXYGEN
 Hydroxylation reactions most common oxidation reactions
reduced CYP 450 oxidised CYP 450
RH + Oշ R-OH + HշO

11. MECHANISM OF ACTION CONTINUED…………..

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

13. NOMENCLATURE…………………………
GENE IS DENOTED IN ITALICS. EG:-CYP 3A4

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

23. AMPLI CHIP CYP450 ARRAY
FIRST PHARMACOGENOMICS DIAGNOSTIC TOOL

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