Metabolism /

Biotransformation of
Xenobiotis/toxicants

Metabolism
Purpose : Elimination of foreign compounds
Major sites: Liver
Process in general
Compounds -> metabolites
Lipid soluble -> water soluble
(hard to excrete) -> easier to be excreted
Result
Inactive metabolite
Relatively non-toxic metabolite
Exception
sometime
Water soluble -> lipid soluble
More toxic metabolite (BIOACTIVATION)

Sites of Metabolism

Liver (Hepatic)
Primary site!
Rich in enzymes
Acts on endogenous and exogenous

compounds
Extrahepatic metabolism sites
Intestinal wall
Bacterial flora

Reduction of Aromatic nitro and azo compounds

Lungs, kidney, placenta, brain, skin, adrenal

glands

Limited ability and largely unknown

Metabolism

hase I:

Modification/functionalization

oxidation
reduction
hydrolysis

Polar metabolite
with functional
OH NH2 SH COOH

Phase II: Conjugation with

ater
lutathion
lucuronic acid
ulfate
mino acids

Hydrophilic
metabolite

Phase I reactions
Functionalization

to Increase polarity of molecules

Purpose

Introduction of polar functional groups in a molecules

Hydroxyl groups
Carboxylate groups
Amino Groups
Thiol Groups

Does provide a site for phase II metabolism

Phase I Metabolism
Enzim yang berperan : Cytochrome P450 enzymes (CYP)
Contoh : CYP 3 A 4, CYP 2 E 1

Hydroxylation -CH2CH3
Oxidation -CH2OH

-CH2CH2OH

-CHO

-COOH
H

CH3

COOH

phase I

phase II

COOH

Phase 1

=parent
compound
=activated
compound

Phase 2
glucorinidation

sulfation

detox

co
um
ar
in

bioactivation

Fig. Biotransformation reactions of coumarin leading to

detoxification (7-hydroxylation and 3-hydroxylation) or metabolic
activation via the coumarin 3,4-epoxide pathway .
8

Activation and de-activation of Aflatoxin B1

Phase II reactions Conjugation

Purpose
Introduce highly polar conjugates
Glucuronic acid
Sulfate
Glycine or other Amino Acids
Glutathione

The conjugates are more polar and

readily excreted in the urine

increased water solubility relative to the

parent compound

Phase II Metabolism

Purpose: Attach polar, ionizable small molecule

Result: Sufficient water solubility for kidney

Reactions
:
excretion
(i) Glucuronidation
(ii) Sulfation

(iii) Glutathione conjugation (gly-cys-glu)

(iv) Amino

Acid Conjugation

H
O

CH3

COOH

phase I

phase II

COOH

Phase 1

=parent
compound
=activated
compound
glucorinidation

sulfation

Phase 2

detox

co
um
ar
in

bioactivation

Fig. Biotransformation reactions of coumarin leading to

detoxification (7-hydroxylation and 3-hydroxylation) or metabolic
activation via the coumarin 3,4-epoxide pathway .
13

Activation and de-activation of Aflatoxin B1

14

Phase
II
metabolism
Glutathione (GSH) Conjugation
DETOXIFICATION of electrophiles!
Electrophilic chemicals cause:
tissue necrosis
Carcinogenicity
Mutagenicity
Teratogenicity
GS enzyme mediator: glutathione

H
O

H+

S-transferase

OH
H
SG

Sulfate Conjugation

Occurs primarily with phenol

Catalyzed by sulfotransferase
NH2
R-OH
N

N
N

HO

O
CH2 O P O SO3O

O- PO3

R-O-SO3-

Glucuronic acid conjugation

Conjugation with glucuronyl group

enzyme : UDP-glucuronyl
transferase
COOH
O
HO OH

R-OH

O
N

O
O
O P O P O CH2
O
OH OH OH

Co-substrat

OH OH

H
O

Phase II Enzyme Reactions

18

Factors influencing enzyme pattern

external factors
diet
smoking habits
use of drugs
exposure to environmental
contaminants
food additives, pesticide
residues

Factors influencing enzyme

pattern
internal factors:
species-dependent differences
organ-specific differences
gender-specific differences
age-dependent differences
genetically determined
differences

 Stop