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