for first MBBS

5. Xenobiotics
• Def: compounds that are foreign
to body
Eg.- a. drugs
b. preservatives, adulterants
b. pesticides, pollutants
c. compounds produced by
bacterial metabolism ( histamine,
tyramine, putrescine etc.)

6. Detoxification
• Is a biochemical process by
which a toxic substance is
converted to
- less harmful &
- more water soluble so that it
can be excreted.
• Site: Liver

8. Phases of detoxification reactions
Phase I
1. Hydroxylation
2. Oxidation
3. Reduction
4. Hydrolysis
5. Dealkylation
6. Epoxidation
Phase II
• Conjugation reactions
1. Conjugation with
a. glucuronic acid
b. Glutathione
c. glycine.
d. Sulfate
e. Acetyl group
f. Methyl group

9. Phase I reaction
1. Hydroxylation
Enzyme - Cytochrome P 450 family
• Superfamily of Heme containing enzymes
• Named so because when exposed to CO,
show peak absorbance at 450nm
• most imp reaction in phase I
• Present in all tissues, highest amount in
liver - SER
• Large no. of Isoforms (≈150)

10. • Mechanism of action :
Monooxygenases/ mixed function oxidases – use O2,
- one atom of oxygen forms – R-OH (R – xenobiotic)
- another enters water
• require NADPH &
• associated with Phosphatidyl choline
•
• RH + O2 R-OH + H2O
• Red. Cyt P450 Ox. Cyt P450
NADP+ NADPH + H+

11. • Eg: metabolism of
- warfarin
- PAH (polycyclic aromatic hydrocarbons)-
cigarette smoke has various aromatic
hydrocarbons
• Inducible enzyme – drugs –phenobarbitone

12. 2. Oxidation
• Eg : Oxidation & detoxification of alcohol
Ethyl alcohol
Alcohol NAD+
Dehydrogenase NADH + H+
Acetaldehyde
Aldehyde NAD+
Dehydrogenase NADH + H+
acetic acid

13. • Oxidation of some compounds may result in
production of more toxic substances
• Eg. Methanol formic acid
• Ethylene glycol oxalic acid

14. 3. Reduction
a. Nitro compounds amines
b. P-nitrophenol 
p- aminophenol
c. Picric acid  Picramic acid

15. 4. Hydrolysis
toxicant is split into smaller molecules.
• Eg:
a. Aspirinsalicylic acid + acetic acid
b. Acetanilide  aniline + acetic acid

16. • Phase 1 reaction - produces a new
metabolite with a reactive OH/ NH2/
COOH group
• Phase 2 reaction- adds a
conjugating agent in its active form
to the reactive group, makes it
nontoxic & easily excretable.

17. Eg : BENZENE

18. PHASE II –
CONJUGATION REACTIONS
• Def: It is a phase II reaction of
xenobiotic metabolism, where
xenobiotic combines with a
substance produced in the body,
so that it becomes hydrophilic &
excretable

19. Conjugating
compound
Active form Enzyme
involved
Xenobiotic
conjugated
Metabolite
1
Glucuronic
acid
UDP- Glucuronic
acid
UDP-glucronyl
transferase
Bilirubin
Benzoic acid
Phenol
Steroids
Bilirubin mono &
diglucuronide
Glucuronic acid
monobenzoate
Phenyl
glucuronide
Steroid
glucuronide
2 Glutathione GSH GSH transferase
Alkyl halides
Aryl halides
Epoxides
Mercapturic acid
derivatives
3 Sulpate PAPS Sulfotransferase
Phenol
Indole
Phenyl sulphate
Indoxyl sulphate

20. Conjugating
compound
Active form Enzyme
involved
Xenobiotic
conjugated
Metabolite
4 Acetyl Acetyl CoA
Acetyl
transferase
INH
Sulphanilamide
Acetylated
products
5 Glycine Glycine -
Benzoic acid
Cholic acid
Hippuric acid
Glycocholic
acid
6 Glutamine Glutamine -
Phenylacetic
acid
Phenyl acetyl
glutamine
7 Methyl SAM
Methyl
transferase
Mercapto-
Ethanol
Pyridine
Methylated
products

21. CONJUGATION REACTIONS
a. GLUCURONIC ACID-
• most common conjugation
• Active form - UDP-glucuronic acid – uronic acid
pathway
• Enz – Microsomal
eg : Aniline, morphine (analgesic), bilirubin
• Conjugated products eliminated in bile
UDP glucuronyl transferase
UDP glucuronic acid + R-OH R-glucuronide + UDP

22. b. SULFATE CONJUGATION
• Active form: PAPS (phosphoadenosine
phosphosulfate)
• Enz: Sulfotransferase
• metabolites eliminated in urine
• phenol + PAPS phenyl sulfate+ PAP
• indole + PAPS  indoxyl sulfate + PAP

23. 3. glutathione conjugation
• Eg: Alkyl or aryl halides
• Epoxides & alkenes
• Cyclophosphamide (anticancer drug)

24. 4. ACETYLATION
- Active form -
Acetyl CoA
- Enz: Acetyl
transferase
1. sulfanilamide
2. Isoniazid

25. 5. CONJUGATION WITH GLYCINE
• benzoic acid  hippuric acid
• Cholic acid -> Glycocholic acid
6. CONJUGATION WITH GLUTAMINE
phenylacteic acid- phenyl acetyl gluatamine

26. 7. Conjugation with methyl group
- Active form : SAM
- Enz: O-methyl transferase
- Eg.-
a. Mercaptoethanol 5 methyl mercaptoethanol
b. Pyridine N methylpyridine
c. Epinephrine Metanephrine
d. Norepinephrine Normetanephrine

27. Alcohol Metabolism
• Absorption: Stomach and intestine
• Excretion: 1% through lungs and urine, rest
oxidized in liver
• 1. Oxidation in liver: by ADH & ALDH
• a. Alcohol dehydrogenase:
• Mutations in this enzyme can lead to
difference in tolerance to alcohol.

28. • b. Aldehyde dehydrogenase:
• Activity of alcohol dehydrogenase is more
than aldehyde dehydrogenase: toxic
acetaldehyde accumulates – cell death

29. • Eg : Oxidation & detoxification of alcohol
Ethyl alcohol
Alcohol NAD+ (cytosolic)
Dehydrogenase NADH + H+
Acetaldehyde
Aldehyde NAD+ (mitochondrial)
Dehydrogenase NADH + H+
acetic acid

30. 2. Oxidation in liver microsomes by
Cyt P450
• This reaction is Inducible
• Responsible for metabolic tolerance to
alcohol in chronic alcoholics

31. Effects of alcoholism
• High NADH/NAD ratio
• Lactic acidosis: due to high NADH
• Hypoglycemia: def of pyruvate: ↓ OAA,
depression of gluconeogenesis
• Ketogenesis: TCA cycle depressed due to
- ↓ OAA, ↓ pyruvate and ↑ NADH & acetyl CoA
• Fatty liver: high acetyl CoA : lipogenesis

32. • Gout: lactic acidosis - ↓ uric acid excretion
• CNS depression

33. Alcoholism & liver
Fatty liver
Cirrhosis
Hepatic coma

34. CNS
• WERNICK’S DISEASE: Thiamine deficiency

35. Lab findings in alcoholism
• GGT and ALT high
• ↓ aldehyde dehydrogenase

36. Smoking
• Cigarette smoke has a potent carcinogen –
Benzo (a)pyrenes – induces DNA –adducts
which can cause mutations
• Other deleterious substances in cigarette
smoke –
- nicotine
- CO
- NO2 &
- carbon soot