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.
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
HISTORY CONTINUED…………………….
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
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