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CYTOCHROME P-450 
IN 
THERAPEUTICS 
Dr. DIVYA G KRISHNAN 
CALICUT MEDICAL COLLEGE
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.
CONTENTS…………………… 
 Introduction 
 History 
 Location 
 Structure 
 Mechanism of action 
 Nomenclature 
 Properties 
 Clinical relevance 
 Summary
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.
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.
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
LOCATION…………………………… 
HEPATOCYTE
LOCATION……………………….
STRUCTURE……………………………
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
MECHANISM OF ACTION CONTINUED…………..
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
NOMENCLATURE………………………… 
GENE IS DENOTED IN ITALICS. EG:-CYP 3A4
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.
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
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)
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.
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.
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
 Pharmacokinetic tolerance 
 Increased metabolism of endogenous substances 
---------------------------------------------------------------------------------- 
- 
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
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
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
AMPLI CHIP CYP450 ARRAY 
FIRST PHARMACOGENOMICS DIAGNOSTIC TOOL
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
Cytochrome p 450 Dr Divya Krishnan

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Cytochrome p 450 Dr Divya Krishnan

  • 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
  • 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 ---------------------------------------------------------------------------------- - 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