•BIOTRANSFORMATION
•DETOXIFICATION
•METABOLISM OF XENOBIOTICS
INTRODUCTION
• Man is continuously exposed to several foreign compounds such as drugs, pollutants,
food additives, cosmetics, pesticides etc.
• Certain unwanted compounds are produced in the large intestine by the bacteria
which enter the circulation.
• These include indole from tryptophan, cadaverine from lysine, tyramine from
tyrosine, phenol from phenylalanine etc.
• In the normal metabolism of the body, certain waste compounds (e.g bilirubin) are
formed.
• A vast majority of the foreign compounds or the unwanted substances, produced in
the body, are toxic and, therefore, they should be quickly eliminated from the body.
•
BIOTRANSFORMATION
• Biotransformation is the process whereby a substance is
changed from one chemical to another (transformed) by a
chemical reaction within the body.
• Detoxification is a biotransformation process in which:
Metabolites of lower toxicity are produced.
• Bioactivation/Entoxication is a biotransformation process in
which Metabolites of higher toxicity are produced
• Detoxification
• Refers to the series of biochemical reactions occurring in the body to convert
the foreign (often toxic) compounds to non-toxic or less toxic, and more easily
excretable forms.
•
• Bioactivation (Entoxication)
• Refers to the series of biochemical reactions occurring in the body to convert
the foreign compounds into metabolites that are more toxic than the parent
substance
• Biotransformation can produce an unusually reactive metabolite that may
interact with cellular macromolecules like DNA. This can lead to very serious
health effects such as cancer or birth defects.
• An example is the biotransformation of vinyl chloride into vinyl chloride
epoxide, which covalently binds to DNA and RNA, a step leading to cancer of
the liver.
Theories to explain detoxication
• Theory of Sherwin: Detoxication mechanisms render so called toxic
compounds less toxic by transforming them into more soluble
derivatives, which are then more easily excreted.
• Theory of Berczeller: Proposed that toxic compounds are made less
toxic by transformation into compounds having a surface tension
nearly like water than the parent compound. In this way toxic
compounds are prevented from accumulating at the surface of
cells, since the non-toxic forms are swept into body fluids and
excreted.
• Theory of Quick: Proposed that the important factor is conversion
of a weakly acidic substance to a strongly acidic one. Kidney can
excrete stronger acids and their salts more readily than weaker
acids.
XENOBIOTICS
• Xenobiotics are a wide variety of foreign chemicals , both
naturally occurring compounds in plant foods, and synthetic
compounds in medicines, food additives, and environmental
pollutants.
• Additives, Adulterants,
• Bilirubin
• Cosmetics
• Drugs, environmental pollutants
• pesticides
• bacterial action (histamine, putrescine, cadaverine, tyramine
and tryptamine)
Mechanisms of Detoxication
• They are mainly of four types:
• Oxidation
• Reduction
• Hydrolysis and
• Conjugation
• Sometimes they may occur independently and in others there may be
combination of these processes.
•
• In many cases, in humans, oxidation and other reactions may be followed by
conjugation.
• In man, detoxication is principally carried out in liver, but to some extent it
can be carried out in kidneys also.
Reactions of xenobiotics
• Present concept is that the reactions of xenobiotics occur in two phases:
• Phase 1: This phase involves the hydroxylation, the major reaction, catalysed by
mono-oxygenases or cytochrome P450 species.
• Other types of reactions in Phase 1 include: reduction and hydrolysis.
• Phase 2: The hydroxylated or other compounds produced in phase 1 are
converted by specific enzymes to various water soluble polar metabolites by
conjugation with
various conjugating agents, viz. Glucuronic acid, “active” sulfate, methylation,
acetylation, etc.
• The overall purpose of these two phases is to increase their water solubility and
thus facilitate their excretion from the body.
PHASES OF BIOTRANSFORMATION
• Phase I Reactions
•
- Oxidation
•
- Reduction
•
- Hydrolysis
• Phase II Reactions
•
- Glucuronic acid conjugation
•
- Sulphate conjugation
•
- Cysteine and glutathione conjugation
•
- Glycine conjugation
•
- Conjugation with other amino acids
•
- Acetylation reaction
•
- Methylation reaction
PHASE I REACTIONS
• 1. Oxidative reactions
• A large number of foreign substances are destroyed in
the body by oxidation.
• Aliphatic as well as aromatic alcohols may be oxidized to
corresponding acids, probably via aldehyde formation.
• In addition certain amines, anilids and drugs also can
undergo oxidation.
• The reaction also include sulfoxidation, N oxidation and
epoxidation
• Examples
• 1. Methyl groups: These groups can be oxidised to form – COOH group through
formation of aldehyde.
•
• 2 Primary aliphatic and aromatic alcohols: They are oxidized to corresponding
acids, e.g.
• 3. Aromatic hydrocarbons: Aromatic hydrocarbons are oxidized to Phenol and
other phenolic compounds.
• Again they are conjugated with glucuronic acid or sulphuric acid and excreted as
corresponding glucuronides and sulphates.
• 4. Aldehydes: Aldehydes are oxidised to form the corresponding acids.
• Anilides: Anilides are oxidised to the corresponding Phenols, e.g. Acetanilide is
present as a constituent of analgesic drugs, which relieves pain. It is oxidised
in the body to form p-acetyl amino phenol.
•
• 7. Sulphur compounds: The sulphur present in organic sulphur compounds is
oxidised to SO4 – which in turn may be excreted in inorganic or organic form or
as neutral (unoxidised) sulphur.
8. Drugs: Certain drugs can be oxidised in the body and are excreted as hydroxy
derivative or salts.
Examples
• Meprobamate: A tranquilizer used in psychiatric disorders is excreted largely as
the oxidation product hydroxy meprobamate.
• • Chloral: Used as a hypnotic. Most of the chloral undergoes reduction and
conjugation; but partly it can be oxidised to form trichloroacetic acid which is
excreted as its salt.
Role of cytochrome P450 species (Monooxygenases)
Most of the oxidation reactions of detoxification are catalyzed by monooxygenases
or cytochrome P450.
This enzyme, also called mixed function oxidase, is associated with the
microsomes.
The usage P450 refers to the absorption peak (at 450 nm), exhibited by the enzyme
when exposed to carbon monoxide.
Most of the reactions of cytochrome P450 involve the addition of a hydroxyl group
to aliphatic or aromatic compounds which may be represented as;
RH + O2 + NADPH
ROH+ H2O+ NADP+
Features of cytochrome P450
1. Multiple forms of cytochromeP450 are believed to exist,
ranging from 20 to 200. At least 6 species have been
isolated and worked in detail.
2. They are all hemoproteins, containing heme as the
prosthetic group.
3. Cytochrome P450 species are found in the highest
concentration in the microsomes of liver. In the adrenal
gland, they occur in mitochondria.
4. The mechanism of action of cytochrome P450 is complex and
is dependent on NADPH.
• 5. The phospholipid phosphatidylcholine is a constituent of
cytochrome P450 system which is necessary for the action of this
enzyme.
• 6. Cytochrome P450 is an inducible enzyme. Its synthesis is increased
by the
• administration of drugs such as phenobarbitol.
•
7. A distinct species namely cytochrome P448 (with absorption peak
at 448 nm) has been studied. lt is specific for the metabolism of
polycyclic aromatic hydrocarbons, hence it is also known as aromatic
hydrocarbon hydroxylase.
Alcohol Metabolism
2. REDUCTION
• Reduction usually does not occur extensively in man. Examples
• Certain aldehydes, e.g. chloral, a hypnotic, principally undergoes reduction in the
body to form corresponding alcohol, which is then conjugated with D-glucuronic
acid and excreted as corresponding glucuronides.
• 2. Aromatic nitrocompounds, e.g. p-nitrobenzaldehyde is reduced to
corresponding amines and excreted after conjugation.
• Note: Certain of the reduced metabolites, instead of being less toxic, may be
more toxic.
• There are quite a number of therapeutic compounds, used as drugs, which
undergo hydrolysis, usually in liver.
•
3. HYDROLYSIS