What it is....?
? Xenobiotic (Gk xenos "stranger") are chemical
--- Content provided by FirstRanker.com ---
substances foreign to the body excluding antigens.? This includes food additives, pesticides, cosmetics,
environmental pollutants and most important drugs.
--- Content provided by FirstRanker.com ---
? Xenobiotics can produce a variety of biological
effects including
--- Content provided by FirstRanker.com ---
- Pharmacological responses- Toxicity
- Immunological responses
- Cancers
SOURCES
--- Content provided by FirstRanker.com ---
Sources of xenobiotics
EXAMPLES
--- Content provided by FirstRanker.com ---
Industrial chemicalsSolvents (benzene, carbon
tetra chloride) detergents,
bleaching agents
--- Content provided by FirstRanker.com ---
Air Pollutants
Tobacco Smoke, Automobile
exhaust
--- Content provided by FirstRanker.com ---
Food Additives and
Colors (butter yellow, azo
--- Content provided by FirstRanker.com ---
Contaminantsdyes) sweeteners (saccharin),
insecticides
--- Content provided by FirstRanker.com ---
Bacterial metabolitesBacterial toxins
Cosmetics
--- Content provided by FirstRanker.com ---
Hair dyes, body spray,
lipstick
Drugs
--- Content provided by FirstRanker.com ---
Aspirin, tranquilizers, OCPs
etc.
Biotransformation and detoxification
--- Content provided by FirstRanker.com ---
? All the biochemical reactions involved in theconversion of foreign, toxic and water
insoluble molecules to non toxic, water soluble
and excretable forms are called Detoxification
--- Content provided by FirstRanker.com ---
/ Biotransformation reactions? In most cases, biotransformation lessens the
toxicity of xenobiotics
--- Content provided by FirstRanker.com ---
? The term "detoxification" is sometimes used
for many of the reactions involved in the
metabolism of xenobiotics
--- Content provided by FirstRanker.com ---
.? Biotransformation is not exactly synonymous with
detoxification, since in many cases, the metabolites are
--- Content provided by FirstRanker.com ---
more toxic than the parent substance. This is known asBIOACTIVATION OR TOXICATION.
Example: biotransformation of vinyl chloride to vinyl
--- Content provided by FirstRanker.com ---
chloride epoxide, which covalently binds to DNA andRNA, a step leading to cancer of the liver.
? Certain xenobiotics e.g. some drugs, are administered as
--- Content provided by FirstRanker.com ---
a precursor (prodrug) which is activated in the body toactive drug. This is an example of biotransformation but
not detoxification.
Biotransformation reactions
--- Content provided by FirstRanker.com ---
? PurposeConverts lipophilic to hydrophilic
compounds
--- Content provided by FirstRanker.com ---
Facilitates excretion? Consequences
Changes in solubility characteristics
Detoxification
Metabolic activation
--- Content provided by FirstRanker.com ---
SITES OF METABOLISM OF XENOBIOTICS
MECHANISM OF METABOLISM OF
--- Content provided by FirstRanker.com ---
XENOBIOTICS? Several biochemical transformation are used by the
liver for the detoxification of xenobiotics and are
--- Content provided by FirstRanker.com ---
classified into two groups
PHASE I REACTION
? The major reaction involved is Oxidation or
--- Content provided by FirstRanker.com ---
hydroxylation and are catalyzed by Cytochrome P450
enzymes also called mono-oxygenases.
--- Content provided by FirstRanker.com ---
? In addition to hydroxylation, a wide range of reactionsalso take place including
Hydrolysis, Reduction
--- Content provided by FirstRanker.com ---
Dehalogenation, Desulfuration,Deamination, Epoxidation, Peroxygenation
.
? PHASE II REACTION
--- Content provided by FirstRanker.com ---
Reactions mainly involve further modificationand conjugation to make the phase I species
more water soluble. It involves
--- Content provided by FirstRanker.com ---
-conjugation with
a. Glucuronic acid
b. Sulfate
c. Acetate
--- Content provided by FirstRanker.com ---
d. glutathionee. methyl
g. certain amino acids
.
--- Content provided by FirstRanker.com ---
XENOBIOTICSMETABOLISM
PHASE I
--- Content provided by FirstRanker.com ---
PHASE II
?Oxidation
--- Content provided by FirstRanker.com ---
Conjugation with?Hydrolysis
a. Glucuronic acid
--- Content provided by FirstRanker.com ---
?Reduction
b. Sulfate
--- Content provided by FirstRanker.com ---
?Dehalogenation,c. Acetate
?Desulfuration,
--- Content provided by FirstRanker.com ---
d. glutathione
?Deamination
--- Content provided by FirstRanker.com ---
e. methyl?Epoxidation,
g. certain amino acids
--- Content provided by FirstRanker.com ---
?Peroxygenation
Xenobiotic-Metabolizing Enzymes (XME)
Phase I
--- Content provided by FirstRanker.com ---
Phase II (Transferases" )
? Cytochromes P450
? Flavin Containing
--- Content provided by FirstRanker.com ---
-Sulfotransferases (ST)
Monooxygenase
--- Content provided by FirstRanker.com ---
- UDP-glucuronosyl-? Epoxide Hydrolase
transferases (UGT)
--- Content provided by FirstRanker.com ---
? Alcohol /Aldehyde
- Glutathione S-
--- Content provided by FirstRanker.com ---
Dehydrogenasestransferases (GST)
? Monoamine Oxidases
--- Content provided by FirstRanker.com ---
? Xanthine oxidaseSome drug
directly enter
--- Content provided by FirstRanker.com ---
phase Imetabolism
Oxidation
--- Content provided by FirstRanker.com ---
ConjugationDRUG
reduction
--- Content provided by FirstRanker.com ---
PHASE I
PHASE II
--- Content provided by FirstRanker.com ---
productsand/or
hydrolysis
--- Content provided by FirstRanker.com ---
Following phase I, theconjugated
drug may be activated ,
--- Content provided by FirstRanker.com ---
drug
is
--- Content provided by FirstRanker.com ---
unchanged , or most oftenusually
inactivated
--- Content provided by FirstRanker.com ---
inactive
Role of Liver
? Main organ involved
--- Content provided by FirstRanker.com ---
? Hepatocytes contain wide variety of enzymesto process xenobiotics
? Enzymes are present in cytosol, endoplasmic
--- Content provided by FirstRanker.com ---
reticulum and to lesser extent in other
organelles
--- Content provided by FirstRanker.com ---
? Each enzyme represents a large family of geneproduct
? Each gene product may be induced by different
--- Content provided by FirstRanker.com ---
xenobiotics
Cytochrome P450
1. Superfamily of heme enzymes (many isoforms) can
--- Content provided by FirstRanker.com ---
catalyze different reaction types, mainly hydroxylation
2. They are so named, because they absorb light at wave
--- Content provided by FirstRanker.com ---
length of 450 nm, when exposed to carbon monoxide3. Occur in most tissues (except of muscles and
erythrocytes)
--- Content provided by FirstRanker.com ---
4. the highest amount in the liver (ER) and enterocytes.
5. In the liver , present in membrane of SER, which
constitute microsomal fraction.
--- Content provided by FirstRanker.com ---
6. In hepatic microsomes, Cyt P450 can compromise as
much as 20% of the total protein.
--- Content provided by FirstRanker.com ---
7. exhibitgenetic
polymorphism
--- Content provided by FirstRanker.com ---
(atypical
biotransformations)
Cytochrome P450
--- Content provided by FirstRanker.com ---
8. They are mono-oxygenases: R
-H + O2 + NADPH + H+ R-OH + H2O
--- Content provided by FirstRanker.com ---
+ NADP+9. NADPH (and not NADH) is the co-enzyme for
all the P450 enzymes.
--- Content provided by FirstRanker.com ---
10. Electrons are transferred from NADPH to
cytochrome P450. This leads to the reductive
--- Content provided by FirstRanker.com ---
activation of molecular oxygen. One atom ofoxygen is inserted into the substrate.
11. can be induced and inhibited
--- Content provided by FirstRanker.com ---
12. At least half of the common drugs we ingest aremetabolized by isoforms of cytochrome P450
.
--- Content provided by FirstRanker.com ---
? Warfarin, a drug to prevent blood clotting. ismetabolized by CYP2C9 which is induced by
phenobarbital
--- Content provided by FirstRanker.com ---
? Grapefruit contains a variety of furanocoumarins,which inhibit cytochrome P450
? Ethanol induces CYP2E1, which metabolises
--- Content provided by FirstRanker.com ---
many
carcinogens.
--- Content provided by FirstRanker.com ---
Thus,the
risk
--- Content provided by FirstRanker.com ---
of
carcinogenicity is increased after the use of ethanol.
--- Content provided by FirstRanker.com ---
.
.
.
--- Content provided by FirstRanker.com ---
PHASE I REACTIONS
Phase I reactions include:
A. Oxidation
B. Reduction
--- Content provided by FirstRanker.com ---
C. Hydrolysis reactionsA. Oxidation
? A large number of foreign substances are
--- Content provided by FirstRanker.com ---
destroyed by oxidation in the body.Examples
- Oxidation of methyl group containing
--- Content provided by FirstRanker.com ---
compounds Methyl group- is oxidized to acidthrough formation of alcohol and aldehyde
? CH3 CH2OH CHO COOH
.
--- Content provided by FirstRanker.com ---
Oxidation of Alcohols-
Primary aliphatic and aromatic alcohols are
oxidized to corresponding acids
--- Content provided by FirstRanker.com ---
? Methanol ---Formaldehyde--- Formic acid
? Ethanol ---Acetaldehyde--- Acetic acid
? BenzoyalAlcohol-- Benzaldehyde --Benzoic
--- Content provided by FirstRanker.com ---
acid--- Content provided by FirstRanker.com ---
METHANOL TOXICITY.
--- Content provided by FirstRanker.com ---
Oxidation of Aromatic HydrocarbonsAromatic hydrocarbons are oxidized to
phenolic compounds, which can further be
conjugated with Glucuronic acid or Sulfuric
--- Content provided by FirstRanker.com ---
acid in phase 2 reactions so as to be excretedthrough urine.
Oxidation of Aldehydes
--- Content provided by FirstRanker.com ---
? Aldehydes are oxidized to corresponding acid. Acid
thus formed is further conjugated in phase 2; e.g.
--- Content provided by FirstRanker.com ---
? Benzoic acid is conjugated with Glycine to formHippuric acid.
? This reaction exclusively takes place in liver.
--- Content provided by FirstRanker.com ---
? Hippuric acid excretion test is undertaken to determinethe detoxification functions of liver.
Oxidation of Anilides
--- Content provided by FirstRanker.com ---
Anilides are oxidized to corresponding phenolse.g.- Acetanilide is a constituent of analgesic
drug. It is oxidized in the body to form p-
Acetyl amino phenol.
--- Content provided by FirstRanker.com ---
Acetanilide p-Acetyl -Amino phenol
Oxidation of Amines
? Many primary aliphatic amines undergo
--- Content provided by FirstRanker.com ---
oxidation to form the corresponding acids and
nitrogen is converted to urea.
? Benzyl amine Benzoic acid + Urea
--- Content provided by FirstRanker.com ---
? Aromatic amines like Aniline is oxidized tocorresponding phenol.
.
--- Content provided by FirstRanker.com ---
? Oxidation of certain compounds may result inthe production of more toxic compounds
(Entoxification). Therefore their formation is
prevented.
--- Content provided by FirstRanker.com ---
For example
? Methanol Formic acid
? Halogenated Alcohol Halogenated Acid
? Ethylene Glycol Oxalic Acid
--- Content provided by FirstRanker.com ---
B) Reduction? Some of the reductases also contain cytochrome P-
450 and are flavoproteins in nature.
--- Content provided by FirstRanker.com ---
? The major group of compounds which are reduced
and detoxified by the liver are nitro compounds.
--- Content provided by FirstRanker.com ---
? These are reduced to their amines, while aldehydes orketones are reduced to alcohols
E.g.
--- Content provided by FirstRanker.com ---
? p- nitrobenzene p- Amino benzene? p- nitro phenol p-Aminophenol
? Picric Acid Picramic Acid
C)Hydrolysis
--- Content provided by FirstRanker.com ---
? Certain therapeutic compounds undergo hydrolysis,Examples
Acetyl Salicylic acid Acetic acid + Salicylic acid
(Aspirin)
Atropine Tropic acid + Tropine
--- Content provided by FirstRanker.com ---
Procaine p- Amino Benzoic acid + Diethylamino ethanol
Phase II - Conjugation
--- Content provided by FirstRanker.com ---
? Conjugation is a process by which the foreignmolecules and their metabolites are coupled with
a conjugating agent and are converted to soluble,
--- Content provided by FirstRanker.com ---
non toxic derivatives which are easily excreted in
urine
--- Content provided by FirstRanker.com ---
? Conjugation reactions can occur independently orcan follow phase 1(hydroxylation) reactions
? Conjugation takes place primarily in liver but can
--- Content provided by FirstRanker.com ---
occur in kidney also
? After conjugation the products are generally
--- Content provided by FirstRanker.com ---
rendered non toxic but in certain conditions theyare left unchanged or become more toxic.
Types of Phase 2 Reactions
--- Content provided by FirstRanker.com ---
1. Glucuronidation2. Sulfation
3. Acetylation
4. Methylation
5. Conjugation with Amino acids
--- Content provided by FirstRanker.com ---
6. Conjugation with G-SH (Glutathione)1) Glucuronidation
? Glucuronidation is the most frequent conjugation
--- Content provided by FirstRanker.com ---
reaction.? UDP-glucuronic acid , is the Glucuronyl donor,
which is formed in the uronic acid pathway of
--- Content provided by FirstRanker.com ---
Glucose metabolism
? The glucuronic acid is added to xenobiotics by
--- Content provided by FirstRanker.com ---
UDPglucuronyl-transferases, present in the endoplasmic reticulum. .
? Glucuronic acid can conjugate with hydroxyls
--- Content provided by FirstRanker.com ---
(both phenolic and alcoholic), carbonyl,
sulfhydryl and amino compounds.
--- Content provided by FirstRanker.com ---
Glucuronidation
Glucuronidation of Bilirubin
.
--- Content provided by FirstRanker.com ---
? Most of the bilirubin excreted in the bile ofmammals is in the form of bilirubin
diglucuronide.
--- Content provided by FirstRanker.com ---
? Bilirubin-UGT activity can be induced by anumber of clinically useful drugs, including
Phenobarbital
2) Sulfation
--- Content provided by FirstRanker.com ---
? The highly polar sulfate conjugates are readily
excreted through urine.
--- Content provided by FirstRanker.com ---
? The sulfate donor is adenosine 3'-phosphate-5'phosphosulfate (PAPS) this compound is called
"active sulfate
--- Content provided by FirstRanker.com ---
? The enzyme is sulfo transferase? Compounds which are conjugated with sulphate
are 1. Phenols 2. Cresols 3. Indole
--- Content provided by FirstRanker.com ---
4. Steroids 5. Oestrogen and Androgens.
--- Content provided by FirstRanker.com ---
3) Acetylation
? Conjugation with acetic acid is taking place with
--- Content provided by FirstRanker.com ---
drugs like sulfanilamide, isoniazid and PAS (paraamino salicylic acid)
? Acetyl-CoA (active acetate) is the acetyl donor.
? These reactions are catalyzed by acetyltransferases
--- Content provided by FirstRanker.com ---
present in the cytosol of various tissues, particularly
liver
--- Content provided by FirstRanker.com ---
? Polymorphic types of acetyltransferases exist,resulting in individuals .
who are classified as slow or
--- Content provided by FirstRanker.com ---
fast acetylators, and influence the rate of clearance of
drugs from blood.
? Slow acetylators are more subject to certain toxic
--- Content provided by FirstRanker.com ---
effects of drug because the drug persists longer in
these individuals.
Compounds conjugated by Acetylation
--- Content provided by FirstRanker.com ---
? Sulphanilamide? PABA (Para Amino Benzoic Acid)
? Isoniazid
4) Methylation
--- Content provided by FirstRanker.com ---
? Amino, hydroxy or thiol groups are methylated.? S- Adenosyl Methionine-SAM (Active Methionine)
acts as a Methyl group donor
--- Content provided by FirstRanker.com ---
? Reactions are called Transmethylation reactions? Enzymes catalyzing the reactions are Methyl
transferases
--- Content provided by FirstRanker.com ---
Catechol-O-Methyl TransferaseEpinephrine+ S-Adenosyl Methionine
--- Content provided by FirstRanker.com ---
S-Adenosyl Homocysteine + Metanephrine
.
--- Content provided by FirstRanker.com ---
.
+ SAH
.
--- Content provided by FirstRanker.com ---
? Methylation decreases the water solubility
rather than increasing it. Metals like mercury
may be methylated, making them more
--- Content provided by FirstRanker.com ---
lipophilic, increasing permeability and causingneurotoxicity
5) Conjugation with Amino acids
A) Conjugation with Glycine
--- Content provided by FirstRanker.com ---
Benzoic acid + Glyine Hippuric acid(Excreted in urine)
Nicotinamide + Glycine Nicotinuric Acid
? Cholic and deoxy Cholic acid are conjugated to form
--- Content provided by FirstRanker.com ---
Glyco cholic acid and Glycodeoxy cholic acid
.
--- Content provided by FirstRanker.com ---
. Approximately 76% of aspirin is metabolized
through amino acid conjugation Salicyluric
acid, the glycine conjugate of salicyclic acid, is
--- Content provided by FirstRanker.com ---
the main metabolite of aspirinASPIRIN
B) Conjugation with Glutamine
--- Content provided by FirstRanker.com ---
Phenyl Acetic acid + Glutamine Phenyl AcetylGlutamine
This reaction is important in patients of Phenyl
--- Content provided by FirstRanker.com ---
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
--- Content provided by FirstRanker.com ---
6. Conjugation with Glutathione
? Glutathione (-glutamyl-cysteinylglycine) is a
--- Content provided by FirstRanker.com ---
tripeptide consisting of glutamic acid, cysteine,
and glycine It detoxify electrophilic chemicals
--- Content provided by FirstRanker.com ---
.? The glutamyl and glycinyl groups belonging to
glutathione are removed by specific Enzymes
--- Content provided by FirstRanker.com ---
? acetyl group (donated by acetyl- CoA) is added to the
amino group of the remaining cysteinyl moiety
--- Content provided by FirstRanker.com ---
? The resulting compound is a mercapturic acid, aconjugate of L acetylcysteine, which is then excreted in
the urine
--- Content provided by FirstRanker.com ---
.? If the potentially toxic xenobiotics were not
conjugated to GSH, they would be free to
--- Content provided by FirstRanker.com ---
combine covalently with DNA, RNA, or cellprotein and could thus lead to serious cell
damage.
? GSH is therefore an important defense
--- Content provided by FirstRanker.com ---
mechanism against certain toxic compounds,
such as some drugs and carcinogens.
Effects of Xenobiotics
--- Content provided by FirstRanker.com ---
? Metabolism of a xenobiotic can result in cellinjury, immunologic damage, or cancer.
? Cell injury (cytotoxicity), can be severe enough to
--- Content provided by FirstRanker.com ---
result in cell death.
? These macromolecular targets include DNA,
--- Content provided by FirstRanker.com ---
RNA, and protein.? The reactive species of a xenobiotic may bind to a
protein, altering its antigenicity.
--- Content provided by FirstRanker.com ---
? The resulting antibodies can then damage the cell
by several immunologic mechanisms that grossly
--- Content provided by FirstRanker.com ---
perturb normal cellular biochemical processes..
? Reactions of activated species of chemical carcinogens
--- Content provided by FirstRanker.com ---
with DNA are of great importance in chemical
carcinogenesis
? Some chemicals (eg, benzo[]pyrene) require activation
--- Content provided by FirstRanker.com ---
by monooxygenases in the endoplasmic reticulum to
become carcinogenic (they are thus called indirect
carcinogens).
--- Content provided by FirstRanker.com ---
? The products of the action of certain monooxygenases onsome procarcinogen substrates are epoxides.
? Epoxides are highly reactive and mutagenic or
--- Content provided by FirstRanker.com ---
carcinogenic or both.
? Epoxide hydrolase--like cytochrome P450acts on these
--- Content provided by FirstRanker.com ---
compounds, converting them into much less reactivedihydrodiols.
...
--- Content provided by FirstRanker.com ---
Summary? Xenobiotics are chemical compounds foreign to the body,
such as drugs, food additives, and environmental pollutants
--- Content provided by FirstRanker.com ---
? Xenobiotics are metabolized in two phases. The major
reaction of phase 1 is hydroxylation catalyzed by a variety
--- Content provided by FirstRanker.com ---
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,
--- Content provided by FirstRanker.com ---
sulfate, or glutathione.
? The combined operation of these two phases renders
--- Content provided by FirstRanker.com ---
lipophilic compounds into water-soluble compounds thatcan be eliminated from the body.
? Xenobiotics can produce a variety of biologic effects,
--- Content provided by FirstRanker.com ---
including pharmacologic responses, toxicity, immunologic
reactions, and cancer
--- Content provided by FirstRanker.com ---