Download MBBS Xenobiotic Lecture PPT

Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Xenobiotic Lecture PPT


What it is....?

? Xenobiotic (Gk xenos "stranger") are chemical

substances foreign to the body excluding antigens.

? This includes food additives, pesticides, cosmetics,

environmental pollutants and most important drugs.

? Xenobiotics can produce a variety of biological

effects including

- Pharmacological responses
- Toxicity
- Immunological responses
- Cancers
SOURCES

Sources of xenobiotics

EXAMPLES

Industrial chemicals

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

Air Pollutants

Tobacco Smoke, Automobile
exhaust

Food Additives and

Colors (butter yellow, azo

Contaminants

dyes) sweeteners (saccharin),
insecticides

Bacterial metabolites

Bacterial toxins

Cosmetics

Hair dyes, body spray,
lipstick

Drugs

Aspirin, tranquilizers, OCPs
etc.
Biotransformation and detoxification

? 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
/ Biotransformation reactions

? In most cases, biotransformation lessens the

toxicity of xenobiotics

? The term "detoxification" is sometimes used

for many of the reactions involved in the
metabolism of xenobiotics
.

? Biotransformation is not exactly synonymous with

detoxification, since in many cases, the metabolites are
more toxic than the parent substance. This is known as
BIOACTIVATION OR TOXICATION.

Example: biotransformation of vinyl chloride to vinyl

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

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

? Purpose
Converts lipophilic to hydrophilic

compounds

Facilitates excretion
? Consequences
Changes in solubility characteristics
Detoxification
Metabolic activation


SITES OF METABOLISM OF XENOBIOTICS
MECHANISM OF METABOLISM OF

XENOBIOTICS

? Several biochemical transformation are used by the

liver for the detoxification of xenobiotics and are

classified into two groups

PHASE I REACTION
? The major reaction involved is Oxidation or

hydroxylation and are catalyzed by Cytochrome P450

enzymes also called mono-oxygenases.

? In addition to hydroxylation, a wide range of reactions

also take place including

Hydrolysis, Reduction
Dehalogenation, Desulfuration,
Deamination, Epoxidation, Peroxygenation
.

? PHASE II REACTION
Reactions mainly involve further modification

and conjugation to make the phase I species

more water soluble. It involves

-conjugation with
a. Glucuronic acid
b. Sulfate
c. Acetate
d. glutathione
e. methyl
g. certain amino acids
.

XENOBIOTICS

METABOLISM

PHASE I

PHASE II

?Oxidation

Conjugation with

?Hydrolysis

a. Glucuronic acid

?Reduction

b. Sulfate

?Dehalogenation,

c. Acetate

?Desulfuration,

d. glutathione

?Deamination

e. methyl

?Epoxidation,

g. certain amino acids

?Peroxygenation
Xenobiotic-Metabolizing Enzymes (XME)

Phase I

Phase II (Transferases" )

? Cytochromes P450
? Flavin Containing

-Sulfotransferases (ST)

Monooxygenase

- UDP-glucuronosyl-

? Epoxide Hydrolase

transferases (UGT)

? Alcohol /Aldehyde

- Glutathione S-

Dehydrogenases

transferases (GST)

? Monoamine Oxidases
? Xanthine oxidase


Some drug
directly enter
phase I
metabolism

Oxidation

Conjugation

DRUG

reduction

PHASE I

PHASE II

products

and/or
hydrolysis

Following phase I, the

conjugated

drug may be activated ,

drug

is

unchanged , or most often

usually

inactivated

inactive
Role of Liver

? Main organ involved
? Hepatocytes contain wide variety of enzymes

to process xenobiotics

? Enzymes are present in cytosol, endoplasmic

reticulum and to lesser extent in other

organelles

? Each enzyme represents a large family of gene

product

? Each gene product may be induced by different

xenobiotics
Cytochrome P450

1. Superfamily of heme enzymes (many isoforms) can

catalyze different reaction types, mainly hydroxylation

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

length of 450 nm, when exposed to carbon monoxide

3. Occur in most tissues (except of muscles and

erythrocytes)

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

constitute microsomal fraction.

6. In hepatic microsomes, Cyt P450 can compromise as

much as 20% of the total protein.

7. exhibit

genetic

polymorphism

(atypical

biotransformations)
Cytochrome P450

8. They are mono-oxygenases: R

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

+ NADP+

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

all the P450 enzymes.

10. Electrons are transferred from NADPH to

cytochrome P450. This leads to the reductive

activation of molecular oxygen. One atom of

oxygen is inserted into the substrate.

11. can be induced and inhibited
12. At least half of the common drugs we ingest are

metabolized by isoforms of cytochrome P450
.

? Warfarin, a drug to prevent blood clotting. is

metabolized by CYP2C9 which is induced by
phenobarbital

? Grapefruit contains a variety of furanocoumarins,

which inhibit cytochrome P450

? Ethanol induces CYP2E1, which metabolises

many

carcinogens.

Thus,

the

risk

of

carcinogenicity is increased after the use of ethanol.


.

.
.

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

? A large number of foreign substances are

destroyed by oxidation in the body.

Examples
- Oxidation of methyl group containing

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

? CH3 CH2OH CHO COOH
.

Oxidation of Alcohols-
Primary aliphatic and aromatic alcohols are

oxidized to corresponding acids

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

acid




METHANOL TOXICITY


.

Oxidation of Aromatic Hydrocarbons

Aromatic hydrocarbons are oxidized to
phenolic compounds, which can further be
conjugated with Glucuronic acid or Sulfuric
acid in phase 2 reactions so as to be excreted
through urine.


Oxidation of Aldehydes

? Aldehydes are oxidized to corresponding acid. Acid

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

? Benzoic acid is conjugated with Glycine to form

Hippuric acid.

? This reaction exclusively takes place in liver.
? Hippuric acid excretion test is undertaken to determine

the detoxification functions of liver.
Oxidation of Anilides

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.

Acetanilide p-Acetyl -Amino phenol
Oxidation of Amines

? Many primary aliphatic amines undergo

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

? Benzyl amine Benzoic acid + Urea
? Aromatic amines like Aniline is oxidized to

corresponding phenol.
.

? Oxidation of certain compounds may result in

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

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

? Some of the reductases also contain cytochrome P-

450 and are flavoproteins in nature.

? The major group of compounds which are reduced

and detoxified by the liver are nitro compounds.

? These are reduced to their amines, while aldehydes or

ketones are reduced to alcohols

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

? Certain therapeutic compounds undergo hydrolysis,
Examples
Acetyl Salicylic acid Acetic acid + Salicylic acid
(Aspirin)
Atropine Tropic acid + Tropine
Procaine p- Amino Benzoic acid + Diethyl

amino ethanol
Phase II - Conjugation

? Conjugation is a process by which the foreign

molecules and their metabolites are coupled with

a conjugating agent and are converted to soluble,

non toxic derivatives which are easily excreted in

urine

? Conjugation reactions can occur independently or

can follow phase 1(hydroxylation) reactions

? Conjugation takes place primarily in liver but can

occur in kidney also

? After conjugation the products are generally

rendered non toxic but in certain conditions they

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

1. Glucuronidation
2. Sulfation
3. Acetylation
4. Methylation
5. Conjugation with Amino acids
6. Conjugation with G-SH (Glutathione)
1) Glucuronidation

? Glucuronidation is the most frequent conjugation

reaction.

? UDP-glucuronic acid , is the Glucuronyl donor,

which is formed in the uronic acid pathway of

Glucose metabolism

? The glucuronic acid is added to xenobiotics by

UDPglucuronyl-transferases, present in the endo

plasmic reticulum. .

? Glucuronic acid can conjugate with hydroxyls

(both phenolic and alcoholic), carbonyl,

sulfhydryl and amino compounds.


Glucuronidation
Glucuronidation of Bilirubin
.

? Most of the bilirubin excreted in the bile of

mammals is in the form of bilirubin
diglucuronide.

? Bilirubin-UGT activity can be induced by a

number of clinically useful drugs, including
Phenobarbital
2) Sulfation

? The highly polar sulfate conjugates are readily

excreted through urine.

? The sulfate donor is adenosine 3'-phosphate-

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

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

are 1. Phenols 2. Cresols 3. Indole

4. Steroids 5. Oestrogen and Androgens


.


3) Acetylation

? Conjugation with acetic acid is taking place with

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

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

present in the cytosol of various tissues, particularly
liver


? Polymorphic types of acetyltransferases exist,

resulting in individuals .

who are classified as slow or

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

? Slow acetylators are more subject to certain toxic

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

Compounds conjugated by Acetylation
? Sulphanilamide
? PABA (Para Amino Benzoic Acid)
? Isoniazid
4) Methylation

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

acts as a Methyl group donor

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

transferases

Catechol-O-Methyl Transferase

Epinephrine+ S-Adenosyl Methionine



S-Adenosyl Homocysteine + Metanephrine


.

.

+ SAH
.

? Methylation decreases the water solubility

rather than increasing it. Metals like mercury
may be methylated, making them more
lipophilic, increasing permeability and causing
neurotoxicity
5) Conjugation with Amino acids

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

? Cholic and deoxy Cholic acid are conjugated to form

Glyco cholic acid and Glycodeoxy cholic acid


.

. Approximately 76% of aspirin is metabolized

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

ASPIRIN
B) Conjugation with Glutamine

Phenyl Acetic acid + Glutamine Phenyl Acetyl

Glutamine

This reaction is important in patients of Phenyl

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


6. Conjugation with Glutathione

? Glutathione (-glutamyl-cysteinylglycine) is a

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


.

? The glutamyl and glycinyl groups belonging to

glutathione are removed by specific Enzymes

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

amino group of the remaining cysteinyl moiety

? The resulting compound is a mercapturic acid, a

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

.

? If the potentially toxic xenobiotics were not

conjugated to GSH, they would be free to
combine covalently with DNA, RNA, or cell
protein and could thus lead to serious cell
damage.

? GSH is therefore an important defense

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

? Metabolism of a xenobiotic can result in cell

injury, immunologic damage, or cancer.

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

result in cell death.

? These macromolecular targets include DNA,

RNA, and protein.

? The reactive species of a xenobiotic may bind to a

protein, altering its antigenicity.

? The resulting antibodies can then damage the cell

by several immunologic mechanisms that grossly

perturb normal cellular biochemical processes.

.

? Reactions of activated species of chemical carcinogens

with DNA are of great importance in chemical
carcinogenesis

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

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

? The products of the action of certain monooxygenases on

some procarcinogen substrates are epoxides.

? Epoxides are highly reactive and mutagenic or

carcinogenic or both.

? Epoxide hydrolase--like cytochrome P450acts on these

compounds, converting them into much less reactive
dihydrodiols.


...
Summary

? Xenobiotics are chemical compounds foreign to the body,

such as drugs, food additives, and environmental pollutants

? Xenobiotics are metabolized in two phases. The major

reaction of phase 1 is hydroxylation catalyzed by a variety

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,

sulfate, or glutathione.

? The combined operation of these two phases renders

lipophilic compounds into water-soluble compounds that

can be eliminated from the body.

? Xenobiotics can produce a variety of biologic effects,

including pharmacologic responses, toxicity, immunologic

reactions, and cancer

This post was last modified on 30 November 2021