1. So far, 74 CYP gene families have
been described, of which three main
ones (CYP1, CYP2, CYP3) are
involved in drug metabolism in
human liver. CYP1A2 is one of the
main enzyme.
(Cytochrome P450 is called ‘super
family’)

2. Drug oxidation by the monooxygenase P450
system requires drug , P450 enzymes, and in
addition molecular O2 , NADPH and a
flavoprotein (NADPH-P450 reductase)

3. Examples of common drugs that are substrate for
P450 isoenzymes
Isoenzyme P450 Drug
CYP1A1 Theophyline
CYP1A2 Caffeine, paracetamol
CYP2A6 Methoxyflurane
CYP2 Taxol
CYP2C9 Ibuprofen, phenytoin,
tolbutamide, warfarin

4. Cont’d…….
CYP2C19 Omeprazole
CYP2D6 Clozepine, codeine
CYP2E1 Alcohol, halothane
CYP3A4/ Losartan, nifedipine,
terfenadine

5. P450 and biological variation
Within the human populations there are major
sources of interindividual variation in P450
enzymes that are of great importance in
therapeutics.
These include genetic polymorphisms:
For example, one variant of the gene CYP2D6
leads to poor or extensive hydroxylation of
debrisoquine, (an antihypertensive drug).

6. Cont’d…..
Environmental factors: enzymes inducers
and inhibitors are present in the diet and
environment. For example, grapefruit and
St John’s wort inhibit drug metabolism:
cardiac dysrythmias.
Cigarette smoke induce P450 enzymes

7. Other enzymes involved
 Amine oxidase
 Epoxide hydratase
 Glucuronyl transferase
 Esterases and Amidases
 Alcohol and aldehyde dehydrogenases
 Sulfotransferases
 Acetyl transferases
 Glutathione-s-transferases
 Methyl transferases
 Monoamine oxidase

8. Induction of microsomal enzyme activity
Many drugs and chemicals
1. Anticonvulsants including phenobarbitone,
rifampicin, glucocorticoids induce CYP3A
isoenzymes
2. Phenobarbitone also induce CYP2B1 and
rifampicin also induce CYP2D6
3. Isoniazid and chronic alcohol consumption
induce CYP2E1

9. 4. Benzopyrine found in cigarette smoke and
industrial pollutants induce CYP1A
isoenzymes
5. Others: DDT(dichloro diphenyl
trichloroethane), phenylbutazone, griseofulvin
etc.

10. Inhibition of the microsomal enzyme activity
 Allopurinol Amiodarone
 Chloramphenicol Cimetidine
 Ciprofloxacine Diltiazem
 Metronidazole Ketokonazole
 Omeprazole MAO inhibitors
 Quinidine
Sulfonamides

11. Phase I reactions or non-synthetic
reaction
Here metabolites are active or inactive
 Alter chemical reactivity
 Increase aqueous polarity
Phase I reaction consist of-
a) Oxidation
b) Reduction
c) Hydrolysis

12. In the phase I reaction, it may result in inactivation,
change in the activity or inactivation of the parent drugs.
In this phase, introducing the drug molecule to polar
group such as -OH, -COOH, -NH2, and –SH.
a) Oxidation
This reaction involves addition of oxygen/negatively
charged radical or removal of hydrogen /positively
charged radical
Two types- 1. Microsomal oxidation 2. Non- microsomal
oxidation

13. a) Oxidation
This reaction involves addition of
oxygen/negatively charged radical or removal of
hydrogen /positively charged radical
Two types- 1. Microsomal oxidation 2. Non-
microsomal oxidation

14. Microsomal oxidation
1. Aromatic hydroxylation
2. Aliphatic hydroxylation
3. N-, O-, or S-dealkylation
4. Epoxidation
5. Desulfuration
6. Deamination
7. Sulfoxidation
8. N—oxidation
9. N- hydroxylation
10. Dehalogenation

15. 1. Aromatic hydroxylation-
Acitanilide ----------- p-hydroxyacetanilide
(paracetamol or acetaminophen)
2. Aliphatic hydroxylation
Phenobarbitone --------- phenobarbitone alcohol
3. Dealkylation:
N-dealkylation-
ex- diazepam -------desmethyldiazepam, here N-
methyl group can be removed oxidatively

16. 4. O-deakylation-
ex- phenacetin ----- paracetamol ( active
metabolites)
5. Epoxidation-
ex- Vitamin k -------- vitamin k epoxide
benzene -------- benzene epoxide
6. Desulfuration-
ex- Melathion -------Parathion ( more toxic than
parent drug)
7. Deamination-
ex- Amphetamine ------- phenylacetone ( inactive )

17. b) Reduction
Drugs those contain- disulphide (s:s), azo (n:n),
or nitro (no2)
Azo-
ex- Prontosil dye ---------- > Sulfanilamide
Nitro-
ex- chloramphenicol --------- > arylamine

18. c) Hydrolysis
Ex- Acetylcholine -------- choline + acetate
Procaine ------------- > p-aminobenzoic acid

19. Phase II or synthetic or conjugation reaction
Six types of phase II reactions.
It occur when a drug or Phase I metabolites contains-
-OH, -COOH, -NH2 , -SH group
(Aim: readily excreted more water soluble polar
metabolites)
Conjugating agents are-
Glucuronic acid, Glycine, cysteine, methionine (for
methylation), sulfate, acetyl (for acetylation)

20. Species variation in conjugation reaction can
depend on occurrence of the conjugating agent,
ability of the body to form the necessary
nucleotide or amount of transferring enzymes.
Certain conjugation reaction are either defective
or absent in particular species.

21. Cont’d…..
Ex.- The cat synthesizes glucuronide
conjugation at a slower rate, as this species is
deficient in the transferring enzyme glucuronyl
transferase
The dog and fox are unable to acetylate
aromatic amino groups

22. Glucuronide conjugation
Drugs and some endogenous substances,
steroid, thyroxine, bilirubin.
First of all, glucuronic acid should be activated.
The activated form of glucuronic acid is the
nucleotide- uridinine diphosphate glucuronic acid
(UDPGA)
The drugs and endogenous substances that are
excreted largely as glucuronides include-

23. The drugs and endogenous substances that are
excreted largely as glucuronides include-
Drugs:
Morphine
Salicylates
Acetaminophen
Chloramphenicol
Phase I metabolites of
diazepam (oxazepam),
phenylbutazone (oxyphebylbutazone)

24. Endogenous substances
Steroid
Bilirubin
Thyroxine

25. Requirement for the formation of glucuronide-
UDPGA, drug or its metabolites and glucuronyl
transferase
Why more water soluble?
Because, large hydrophilic carbohydrate moiety
and more highly ionized at physiological pH
values