Cytochrome p450

Cytochrome p450 in Psychiatry

1. Cytochrome P450

2. History
•1947 : R.T. Williams - in vivo
•Axelrod and Brodie et al., who identified an enzyme system
in the endoplasmic reticulum of the liver which was able to
oxidize xenobiotic compounds
•Garfinkel and Klingenberg detected a CO binding pigment
in liver microsomes which had an absorption maximum at
450nm
•P450cam structure was solved in 1987

3. Introduction
•The cytochrome P450 superfamily (officially abbreviated
as CYP) is a large and diverse group of enzymes. The function of
most CYP enzymes is to catalyze the oxidation of organic
substances
•The substrates of CYP enzymes include metabolic intermediates
such as lipids & steroidal hormones, as well
as xenobiotic substances such as drugs and other toxic chemicals.

•75% of the total number of different metabolic reactions.

4. •The most common reaction is catalysed by CYP450 is a
monooxygenase reaction
•Example: insertion of one atom of oxygen into an organic
substrate (RH) while the other oxygen atom is reduced to
water
RH + O
2 + NADPH + H
+
→ ROH + H
2O + NADP
+

RH represents an oxidisable drug substrate
ROH is the hydroxylated metabolite

5. •Cytochromes P450 (CYPs) belong to the superfamily of
proteins containing a heme cofactor. Hence hemoproteins.
•CYPs use a variety of small and large molecules
as substrates in enzymatic reactions.
•Part of multi-component electron transfer chains
•Cytochromes P450 have been named on the basis of their
cellular (cyto) location and spectrophotometric charecteristics
(chrome)
•Reduced heme iron combines with CO, P450 enzymes absorb
light at wavelengths near 450 nm (Soret peak)

6. •Found in every class of organism, including Archaea
•The p450 superfamily is believed to have originated from an
ancestral gene that existed over 3 billion years ago
•In humans
•Central role in phase I drug metabolism
•Significant problems in clinical pharmacology
•Drug interactions
•Inter individual variability in drug metabolism
•Genetic polymorphism resulting in marked variation in human
metabolic activity E.g.. CYP2D6

7. Cytochrome p450s
•Oxidative
•Peroxidative
•Reductive metabolism of
•Xenobiotic substrates as environmental pollutants, agrochemicals, plant
allelochemicals
•Xenobiotic compounds such as drugs, carcinogens and endobiotics
•Endogenous compounds
•Steroids & prostaglandins
•Fatty acids

8. Nomenclature
•Abbreviated as CYP, followed by Arabic numeral indicating the gene
family, a capital letter indicating the subfamily, and another numeral
for the individual gene
•Genes Italics
•EnzymesBold alphabets

9. Location of CYP450
•Distributed all throughout the human body
•Maximum concentration is in the liver
•Why in liver? Metabolism
•Where in liver? Mitochondria & ER

10. Functions
•To function within phase I Liver Detoxification
•To detoxify xenobiotic sources of toxicity, chemicals, alcohols
and carinogens, converting them into water and oxygen
•To assist endogenous sources of waste such as Bilirubin
•To assist in the synthesis of Vitamin D
•For hormone synthesis: To effectively convert cholesterol into
pregnenelone which then gets converted into other hormones like
estrogen, testosterone, cortisol and DHEA
•For the synthesis of bile and bile acids, which are necessary for
the assimilation of fat soluble vitamins. Bile also contains many
of the toxins conjugated in the liver, which then get dumped into
the bowels for proper elimination

11. CORE CONCEPTS

12. Drugs
Inactive Active
Active Inactive
Active Partially active

13. Enzymatic Processes
1.Enzyme induction
2.Enzyme inhibition
3.Auto Induction

14. Drug-Drug interactions : 6 patterns
Pattern 1: An inhibitor is added to a substrate
•Example: Paroxetine is added to nortriptyline, leading to an increase in the
nortriptyline blood level.
Pattern 2: A substrate is added to an inhibitor
•Example: Nortriptyline is added to paroxetine, leading to a higher than
expected blood level of nortriptyline at a given dose.

15. Pattern 3: An inducer is added to a substrate
•Example: Carbamazepine is added to is haloperidol, leading to a decrease
in the haloperidol blood level.
Pattern 4: A substrate is added to an inducer
•Example: Haloperidol is added to carbamazepine, leading to a lower than ,
expected blood level of haloperidol at a given dose.

16. Pattern 5: Reversal of inhibition.
•An inhibitor and a substrate have been stably co-administered and
then the inhibitor is discontinued.
•Example: Cimetidine is discontinued in the presence of
nortriptyline, leading to a decrease in the nortriptyline blood level.

17. Pattern 6: Reversal of induction.
•An inducer and a substrate have been stably co-administered and
then the inducer is discontinued.
•Example: A patient on clozapine abruptly abruptly discontinues
smoking, leading to an increase in the clozapine blood level

18. •Is p450 Induction Limited to Drugs?
No. In fact, grapefruit juice can inhibit CYP3A4 mediated
metabolism. Alcohol, chronic cigarette smoking, and even
charbroiled meats can induce hepatic CYP450 enzymes.

19. Isoforms
•CYP450
•11,500 subtypes identified in various species
•In humans, more than 50 isoforms are identified
•But a few are clinically significant
•CYP1A2
•CYP2D6
•CYP2C9
•CYP2C19
•CYP3A4

20. BASIC CONCEPTS
STEPHEN M. STAHL

21. 5 significant isoforms
•CYP1A2
•CYP2D6
•CYP2C9
•CYP2C19
•CYP3A4

22. CYP450 1A2
•Substrates : Clozapine, olanzapine, zotepine, Halo, Dulox, TCA
•Inhibitor : Fluvoxamine > 10 fold clozapine , zotepine ::: Seizures
•Inducers : Smoking
•TCA, Duloxetine, theophyllin toxicity with fluvoxamine
•TCA Less Active Metabolite
•1A2 : demethylation

23. CYP450 2C9
•DPA: bifeprunox (substrate), Fluox, Pheny, Warfarin
•Inhibitor : fluconazole
•Inducer: Pheno
•Increases the levels l/t toxicicity

24. CYP450 2D6
•Risperidone, Clozapine, Olanzapine, Aripiprazole,Donepezil,
Dulox,Fluox, Galantamine, Mirta, Parox, TCA, FGA, Velna
•Risperidone Paliperidone
•Inhibitors : Paroxetine, Fluoxetine, duloxetine, hd sertraline
•Inhibitors l/t EPS
•Atomoxetine inactive metabolite
•TCA less active metabolite
•2D6 : Hydroxylation

25. CYP450 2D6
•Venlafaxin Desvenlafaxin (active )
•Caution : “TCAs with SSRIs”

26. CYP450 3A4
•Substrates : Clozapine, Quetiapine, Ziprasidone, Sertindole,
Aripiprazole, Zotepine,BZD,CCB,BB,Carba,Reboxetine,TCA
•Inhibitors : Ketaconazole, Erythromycin, Nefazadone, Fluvoxamine,
Fluoxetine, Protease inhibitors
•Carbamazepine: Inducer
•Auto induction on chronic use
•Dose increased w CBZ use
•Dose reduction w CBZ withdrawal

27. CYP450 3A4 (Antidepressants)
Substrates
•Pimozide & CBZ
•Alprazolam
•Triazolam
•Buspirone
•HMG-CoA reductase inhibitors
•Simvastatin
•Atorvastatin
•Lovaststin
Inhibitors
•Fluvoxamine
•Fluoxetine
•Nefazedone
•Erythromycin
•Ketaconazole
•Protease inhibitors
•Note: Sertraline is a weak inhibitor of
CYP4502D6

28. •Pimozide: QTc prolongation & Arrythmias
•CBZ, Alprazolam, triazolam : sedation
•HMG CoA RI : rhabdomyolysis
•Note:
•Escitalopram is the best tolerated SSRI with the fewest CYP450-
mediated interactions

29. Substrates, Inhibitors and Inducers of
CYP2E1 Substrates
•Substrates
•Acetaminophen (Tylenol)
•Ethanol
•Inhibitors
•Disulfiram (Antabuse)
•Inducers
•Ethanol
•Isoniazid (Laniazid)

30. Thank you