Xenobiotics are foreign compounds to our body. They are more lipophilic and less hydrophilic . So it is quite tough to excrete them out from the body. Hence metabolism of xenobiotic is important.
3. •
Food additives, poisons, toxins,
certain drugs, chemicals,
environmental pollutants, pesticides
and other foreign substances
4. The purpose of metabolism is to convert:
Less water soluble xenobiotics into more soluble ones
Toxic xenobiotics into non-toxic or less toxic ones
The relatively soluble metabolite are excreted, mainly in urine
or bile.
5. Liver is the major site for metabolism of xenobiotics. The metabolic reactions
can be divided into two phases – phase 1 and phase 2
tissues as well
metabolism can occur in some other tissues as well
metabolic reactions
Phase 1 Phase 2
Some xenobiotics are excreted directly after phase 1 reactions.
In most cases, phase 1 reactions are followed by phase 2 reactions
6. Xenobiotics
(Lipid soluble,
water insoluble)
Oxidation, Reduction,
Hydrolysis
Phase I
Final Products
(Water soluble)
Excretion in Urine, Feces & Sweat
Intermediate
(Polar)
Phase II
Glucuronic acid, Glutathione, Sulphate,
Acetate, Methyl etc.
Conjugation
7. Phase 1 reactions
The main phase 1 reactions are:
Hydroxylation
Oxidation
Reduction
Hydration
8. Hydroxylation
Hydroxylation is the major reaction in phase 1
It is catalyzed by the microsomal hydroxylase system
This system is associated with the membrane of endoplasmic reticulum
Microsomal hydroxylase system consists of:
Cytochrome P-450 (abbreviated as CYP)
NADPH
FAD
FMN
9. Substrate and an O2 molecule bind
to CYP
One oxygen atom is introduced
into the substrate
The other oxygen atom reacts with
two hydrogen atoms to form water
The hydrogen atoms are provided
by NADPH, and pass via FAD
and FMN
10. The overall reaction catalyzed by the microsomal hydroxylase system may
be summed up as:
XH + O2 + NADPH + H+→ X–OH + H2O + NADP+
The chemical groups that are hydroxylated include methyl group, phenyl
group, amino group, unsaturated aliphatic group etc.
Codeine is converted into morphine by hydroxylation
of its O-methyl group.
R-O-CH3 R-OH + HCHO
11. Oxidation
Ethanol and methanol are oxidized to
acetaldehyde and formaldehyde
respectively by alcohol dehydrogenase
Acetaldehyde and formaldehyde are
oxidized to acetic acid and formic acid
respectively by aldehyde
dehydrogenase.
The common enzymes that metabolize
these two have a greater affinity for
ethanol than for methanol
12. Methanol is oxidized to more toxic formaldehyde and formic acid. These can cause atrophy of optic
nerves.
Metabolites of ethanol are non-toxic; hence ethanol is used to treat methanol poisoning.
Non Microsome oxidation system include:
Mitochondrial: Cyt P450, Aldehyde dehydrogenase
Cytosol : Alcohol dehydrogenase
14. HYDROLYSIS
Esters, amines, hydrazines, amides, glycosidic bonds and carbamates
are get hydrolyzed by hydrolysis.
e.g. Aspirin, acetanilide, procaine, xylocaine, aliphatic esters etc.
15. Phase II
CONJUGATION
REACTIONS
In phase 1 reactions, xenobiotics are generally converted to more polar,
hydroxylated derivatives.
In phase 2 reactions, these derivatives are conjugated with molecules such as
glucuronic acid, sulfate, or glutathione.
This renders them even more hydrophilic, and they are eventually excreted in the
urine or bile.
16. Conjugation with glucuronic acid
Glucuronic acid can conjugate the xenobiotic compound having hydroxyl group, Sulphydryl group
amine group, carbonyl group after the phase 1 reaction and then these conjugated compound get
excreted easily.
Formation of UDP – Glucuronate:
17. UDP-glucuronic acid is the glucuronyl donor,
and glucuronosyl transferases, present in both
the endoplasmic reticulum and cytosol, is the
catalyst.
Molecules such as 2-acetylaminofluorene (a
carcinogen), aniline, benzoic acid, phenol, and
many steroids are excreted as glucuronides.
The glucuronide may be attached to oxygen,
nitrogen, or sulfur groups of the substrates.
Glucuronidation is probably the most frequent
conjugation reaction.
18. CYP450Phase 1
Phase 2 UDP glucuronate
transferase
Here we have detailed example
of phenytoin
19. 2. Conjugation with cysteine of Glutathione
Glutathione is a tripeptide consisting of glutamic acid, cysteine, and glycine.
Glutathione is commonly abbreviated GSH (because Conjugation occurs with
the sulphydryl group of cysteine residue of glutathione).
20. A number of potentially toxic electrophilic
xenobiotics (such as alkyl halide,
epoxides) are conjugated by nucleophilic
GSH, that can be represented as follows:
The enzymes catalyzing these reactions
are called glutathione S transferases, are
present in high amounts in liver cytosol
and in lower amounts in other tissues.
g Glutamyl transferase
Cysteinyl glycinase
Glycine
Acetyl - CoA
2
NH2
21. 3. Acetylation:
Acetylation is represented by
X + Acetyl - CoA→ Acetyl -X + CoA
where X represents a xenobiotic.
These reactions are catalysed by acetyl transferases, present in the cytosol of various tissues,
particularly liver.
e.g. The drug isoniazid, used in the treatment of tuberculosis, is subject to acetylation
22. 4. Conjugation with sulphate
Some alcohols and phenols are conjugated with sulphate
The sulphate is provided by phospho- adenosine phosphosulphate (PAPS)
It is added to xenobiotics by sulpho-transferases
Oxidation Sulpho transferase
More hydrophilic
Easily excreted
23. 5. Methylation:
A few xenobiotics are subject to methylation by methyltransferases, employing S-
adenosylmethionine (SAM) as methyl donor.
