This document discusses xenobiotics, the phases of detoxification reactions, and some specific examples. It defines xenobiotics as compounds foreign to the body, like drugs, pesticides, and bacterial metabolites. Detoxification converts toxic substances into less harmful and more water-soluble forms to be excreted, primarily through the liver. There are two phases: phase I uses oxidation, reduction and other reactions, while phase II involves conjugating the substance with glucuronic acid, glutathione, sulfate or other groups to make it excretable. Specific enzyme systems and examples of compounds metabolized are provided for several phase I and II reactions.

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