Download MBBS Xenobiotic Lecture PPT

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substances foreign to the body excluding antigens.

? This includes food additives, pesticides, cosmetics,

environmental pollutants and most important drugs.

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? Xenobiotics can produce a variety of biological

effects including

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- Pharmacological responses
- Toxicity
- Immunological responses
- Cancers
SOURCES

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Sources of xenobiotics

EXAMPLES

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Industrial chemicals

Solvents (benzene, carbon
tetra chloride) detergents,
bleaching agents

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Air Pollutants

Tobacco Smoke, Automobile
exhaust

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Food Additives and

Colors (butter yellow, azo

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Contaminants

dyes) sweeteners (saccharin),
insecticides

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Bacterial metabolites

Bacterial toxins

Cosmetics

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Hair dyes, body spray,
lipstick

Drugs

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Aspirin, tranquilizers, OCPs
etc.
Biotransformation and detoxification

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? All the biochemical reactions involved in the

conversion of foreign, toxic and water
insoluble molecules to non toxic, water soluble
and excretable forms are called Detoxification

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/ Biotransformation reactions

? In most cases, biotransformation lessens the

toxicity of xenobiotics

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? The term "detoxification" is sometimes used

for many of the reactions involved in the
metabolism of xenobiotics

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.

? Biotransformation is not exactly synonymous with

detoxification, since in many cases, the metabolites are

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more toxic than the parent substance. This is known as
BIOACTIVATION OR TOXICATION.

Example: biotransformation of vinyl chloride to vinyl

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chloride epoxide, which covalently binds to DNA and
RNA, a step leading to cancer of the liver.

? Certain xenobiotics e.g. some drugs, are administered as

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a precursor (prodrug) which is activated in the body to
active drug. This is an example of biotransformation but
not detoxification.
Biotransformation reactions

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? Purpose
Converts lipophilic to hydrophilic

compounds

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Facilitates excretion
? Consequences
Changes in solubility characteristics
Detoxification
Metabolic activation

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SITES OF METABOLISM OF XENOBIOTICS
MECHANISM OF METABOLISM OF

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XENOBIOTICS

? Several biochemical transformation are used by the

liver for the detoxification of xenobiotics and are

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classified into two groups

PHASE I REACTION
? The major reaction involved is Oxidation or

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hydroxylation and are catalyzed by Cytochrome P450

enzymes also called mono-oxygenases.

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? In addition to hydroxylation, a wide range of reactions

also take place including

Hydrolysis, Reduction

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Dehalogenation, Desulfuration,
Deamination, Epoxidation, Peroxygenation
.

? PHASE II REACTION

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Reactions mainly involve further modification

and conjugation to make the phase I species

more water soluble. It involves

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-conjugation with
a. Glucuronic acid
b. Sulfate
c. Acetate

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d. glutathione
e. methyl
g. certain amino acids
.

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XENOBIOTICS

METABOLISM

PHASE I

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PHASE II

?Oxidation

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Conjugation with

?Hydrolysis

a. Glucuronic acid

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?Reduction

b. Sulfate

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?Dehalogenation,

c. Acetate

?Desulfuration,

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d. glutathione

?Deamination

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e. methyl

?Epoxidation,

g. certain amino acids

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?Peroxygenation
Xenobiotic-Metabolizing Enzymes (XME)

Phase I

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Phase II (Transferases" )

? Cytochromes P450
? Flavin Containing

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-Sulfotransferases (ST)

Monooxygenase

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- UDP-glucuronosyl-

? Epoxide Hydrolase

transferases (UGT)

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? Alcohol /Aldehyde

- Glutathione S-

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Dehydrogenases

transferases (GST)

? Monoamine Oxidases

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? Xanthine oxidase


Some drug
directly enter

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phase I
metabolism

Oxidation

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Conjugation

DRUG

reduction

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PHASE I

PHASE II

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products

and/or
hydrolysis

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Following phase I, the

conjugated

drug may be activated ,

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drug

is

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unchanged , or most often

usually

inactivated

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inactive
Role of Liver

? Main organ involved

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? Hepatocytes contain wide variety of enzymes

to process xenobiotics

? Enzymes are present in cytosol, endoplasmic

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reticulum and to lesser extent in other

organelles

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? Each enzyme represents a large family of gene

product

? Each gene product may be induced by different

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xenobiotics
Cytochrome P450

1. Superfamily of heme enzymes (many isoforms) can

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catalyze different reaction types, mainly hydroxylation

2. They are so named, because they absorb light at wave

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length of 450 nm, when exposed to carbon monoxide

3. Occur in most tissues (except of muscles and

erythrocytes)

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4. the highest amount in the liver (ER) and enterocytes.
5. In the liver , present in membrane of SER, which

constitute microsomal fraction.

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6. In hepatic microsomes, Cyt P450 can compromise as

much as 20% of the total protein.

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7. exhibit

genetic

polymorphism

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(atypical

biotransformations)
Cytochrome P450

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8. They are mono-oxygenases: R

-H + O2 + NADPH + H+ R-OH + H2O

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+ NADP+

9. NADPH (and not NADH) is the co-enzyme for

all the P450 enzymes.

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10. Electrons are transferred from NADPH to

cytochrome P450. This leads to the reductive

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activation of molecular oxygen. One atom of

oxygen is inserted into the substrate.

11. can be induced and inhibited

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12. At least half of the common drugs we ingest are

metabolized by isoforms of cytochrome P450
.

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? Warfarin, a drug to prevent blood clotting. is

metabolized by CYP2C9 which is induced by
phenobarbital

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? Grapefruit contains a variety of furanocoumarins,

which inhibit cytochrome P450

? Ethanol induces CYP2E1, which metabolises

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many

carcinogens.

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Thus,

the

risk

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of

carcinogenicity is increased after the use of ethanol.

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.

.
.

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PHASE I REACTIONS
Phase I reactions include:
A. Oxidation
B. Reduction

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C. Hydrolysis reactions
A. Oxidation

? A large number of foreign substances are

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destroyed by oxidation in the body.

Examples
- Oxidation of methyl group containing

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compounds Methyl group- is oxidized to acid
through formation of alcohol and aldehyde

? CH3 CH2OH CHO COOH
.

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Oxidation of Alcohols-
Primary aliphatic and aromatic alcohols are

oxidized to corresponding acids

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? Methanol ---Formaldehyde--- Formic acid
? Ethanol ---Acetaldehyde--- Acetic acid
? BenzoyalAlcohol-- Benzaldehyde --Benzoic

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acid

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METHANOL TOXICITY


.

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Oxidation of Aromatic Hydrocarbons

Aromatic hydrocarbons are oxidized to
phenolic compounds, which can further be
conjugated with Glucuronic acid or Sulfuric

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acid in phase 2 reactions so as to be excreted
through urine.


Oxidation of Aldehydes

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? Aldehydes are oxidized to corresponding acid. Acid

thus formed is further conjugated in phase 2; e.g.

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? Benzoic acid is conjugated with Glycine to form

Hippuric acid.

? This reaction exclusively takes place in liver.

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? Hippuric acid excretion test is undertaken to determine

the detoxification functions of liver.
Oxidation of Anilides

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Anilides are oxidized to corresponding phenols

e.g.- Acetanilide is a constituent of analgesic
drug. It is oxidized in the body to form p-
Acetyl amino phenol.

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Acetanilide p-Acetyl -Amino phenol
Oxidation of Amines

? Many primary aliphatic amines undergo

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oxidation to form the corresponding acids and
nitrogen is converted to urea.

? Benzyl amine Benzoic acid + Urea

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? Aromatic amines like Aniline is oxidized to

corresponding phenol.
.

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? Oxidation of certain compounds may result in

the production of more toxic compounds
(Entoxification). Therefore their formation is
prevented.

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For example
? Methanol Formic acid
? Halogenated Alcohol Halogenated Acid
? Ethylene Glycol Oxalic Acid

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B) Reduction

? Some of the reductases also contain cytochrome P-

450 and are flavoproteins in nature.

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? The major group of compounds which are reduced

and detoxified by the liver are nitro compounds.

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? These are reduced to their amines, while aldehydes or

ketones are reduced to alcohols

E.g.

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? p- nitrobenzene p- Amino benzene
? p- nitro phenol p-Aminophenol
? Picric Acid Picramic Acid
C)Hydrolysis

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? Certain therapeutic compounds undergo hydrolysis,
Examples
Acetyl Salicylic acid Acetic acid + Salicylic acid
(Aspirin)
Atropine Tropic acid + Tropine

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Procaine p- Amino Benzoic acid + Diethyl

amino ethanol
Phase II - Conjugation

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? Conjugation is a process by which the foreign

molecules and their metabolites are coupled with

a conjugating agent and are converted to soluble,

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non toxic derivatives which are easily excreted in

urine

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? Conjugation reactions can occur independently or

can follow phase 1(hydroxylation) reactions

? Conjugation takes place primarily in liver but can

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occur in kidney also

? After conjugation the products are generally

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rendered non toxic but in certain conditions they

are left unchanged or become more toxic.
Types of Phase 2 Reactions

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1. Glucuronidation
2. Sulfation
3. Acetylation
4. Methylation
5. Conjugation with Amino acids

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6. Conjugation with G-SH (Glutathione)
1) Glucuronidation

? Glucuronidation is the most frequent conjugation

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reaction.

? UDP-glucuronic acid , is the Glucuronyl donor,

which is formed in the uronic acid pathway of

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Glucose metabolism

? The glucuronic acid is added to xenobiotics by

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UDPglucuronyl-transferases, present in the endo

plasmic reticulum. .

? Glucuronic acid can conjugate with hydroxyls

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(both phenolic and alcoholic), carbonyl,

sulfhydryl and amino compounds.

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Glucuronidation
Glucuronidation of Bilirubin
.

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? Most of the bilirubin excreted in the bile of

mammals is in the form of bilirubin
diglucuronide.

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? Bilirubin-UGT activity can be induced by a

number of clinically useful drugs, including
Phenobarbital
2) Sulfation

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? The highly polar sulfate conjugates are readily

excreted through urine.

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? The sulfate donor is adenosine 3'-phosphate-

5'phosphosulfate (PAPS) this compound is called
"active sulfate

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? The enzyme is sulfo transferase
? Compounds which are conjugated with sulphate

are 1. Phenols 2. Cresols 3. Indole

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4. Steroids 5. Oestrogen and Androgens


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3) Acetylation

? Conjugation with acetic acid is taking place with

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drugs like sulfanilamide, isoniazid and PAS (para
amino salicylic acid)

? Acetyl-CoA (active acetate) is the acetyl donor.
? These reactions are catalyzed by acetyltransferases

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present in the cytosol of various tissues, particularly
liver

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? Polymorphic types of acetyltransferases exist,

resulting in individuals .

who are classified as slow or

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fast acetylators, and influence the rate of clearance of
drugs from blood.

? Slow acetylators are more subject to certain toxic

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effects of drug because the drug persists longer in
these individuals.

Compounds conjugated by Acetylation

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? Sulphanilamide
? PABA (Para Amino Benzoic Acid)
? Isoniazid
4) Methylation

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? Amino, hydroxy or thiol groups are methylated.
? S- Adenosyl Methionine-SAM (Active Methionine)

acts as a Methyl group donor

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? Reactions are called Transmethylation reactions
? Enzymes catalyzing the reactions are Methyl

transferases

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Catechol-O-Methyl Transferase

Epinephrine+ S-Adenosyl Methionine

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S-Adenosyl Homocysteine + Metanephrine


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.

+ SAH
.

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? Methylation decreases the water solubility

rather than increasing it. Metals like mercury
may be methylated, making them more

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lipophilic, increasing permeability and causing
neurotoxicity
5) Conjugation with Amino acids

A) Conjugation with Glycine

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Benzoic acid + Glyine Hippuric acid
(Excreted in urine)
Nicotinamide + Glycine Nicotinuric Acid

? Cholic and deoxy Cholic acid are conjugated to form

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Glyco cholic acid and Glycodeoxy cholic acid


.

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. Approximately 76% of aspirin is metabolized

through amino acid conjugation Salicyluric
acid, the glycine conjugate of salicyclic acid, is

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the main metabolite of aspirin

ASPIRIN
B) Conjugation with Glutamine

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Phenyl Acetic acid + Glutamine Phenyl Acetyl

Glutamine

This reaction is important in patients of Phenyl

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ketonuria, since excess of Phenyl acetic acid leads
to formation of excess of Phenyl acetyl glutamine,
which is excreted in urine, that imparts a mousy
odor to the urine

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6. Conjugation with Glutathione

? Glutathione (-glutamyl-cysteinylglycine) is a

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tripeptide consisting of glutamic acid, cysteine,
and glycine It detoxify electrophilic chemicals

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.

? The glutamyl and glycinyl groups belonging to

glutathione are removed by specific Enzymes

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? acetyl group (donated by acetyl- CoA) is added to the

amino group of the remaining cysteinyl moiety

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? The resulting compound is a mercapturic acid, a

conjugate of L acetylcysteine, which is then excreted in
the urine

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.

? If the potentially toxic xenobiotics were not

conjugated to GSH, they would be free to

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combine covalently with DNA, RNA, or cell
protein and could thus lead to serious cell
damage.

? GSH is therefore an important defense

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mechanism against certain toxic compounds,
such as some drugs and carcinogens.
Effects of Xenobiotics

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? Metabolism of a xenobiotic can result in cell

injury, immunologic damage, or cancer.

? Cell injury (cytotoxicity), can be severe enough to

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result in cell death.

? These macromolecular targets include DNA,

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RNA, and protein.

? The reactive species of a xenobiotic may bind to a

protein, altering its antigenicity.

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? The resulting antibodies can then damage the cell

by several immunologic mechanisms that grossly

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perturb normal cellular biochemical processes.

.

? Reactions of activated species of chemical carcinogens

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with DNA are of great importance in chemical
carcinogenesis

? Some chemicals (eg, benzo[]pyrene) require activation

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by monooxygenases in the endoplasmic reticulum to
become carcinogenic (they are thus called indirect
carcinogens).

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? The products of the action of certain monooxygenases on

some procarcinogen substrates are epoxides.

? Epoxides are highly reactive and mutagenic or

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carcinogenic or both.

? Epoxide hydrolase--like cytochrome P450acts on these

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compounds, converting them into much less reactive
dihydrodiols.


...

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Summary

? Xenobiotics are chemical compounds foreign to the body,

such as drugs, food additives, and environmental pollutants

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? Xenobiotics are metabolized in two phases. The major

reaction of phase 1 is hydroxylation catalyzed by a variety

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of monooxygenases, also known as the cytochrome P450s.

? In phase 2, the hydroxylated species are conjugated with a

variety of hydrophilic compounds such as glucuronic acid,

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sulfate, or glutathione.

? The combined operation of these two phases renders

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lipophilic compounds into water-soluble compounds that

can be eliminated from the body.

? Xenobiotics can produce a variety of biologic effects,

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including pharmacologic responses, toxicity, immunologic

reactions, and cancer