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2. COURSE CONTENTS
ENVIRONMENTAL TOXICOLOGY ZOL 610 3(2-1)
Toxicology: History , Terms and definitions, principles of
Toxicology, Development and present scope of
environmental toxicology, Framework of environmental
toxicology, toxicological evaluation, Sources of
environmental toxicants, / Pollutants: Gaseous chemicals
and heavy metals, toxicity testing,
Characteristics of exposure, spectrum of Toxic effects,
Indices of toxicity, toxico-dynamics, toxico-kinetics
(absorption, distribution and elimination of toxic agents)
Biotransformation, Detoxification and biodegradation.
Pollution and remediation, ecological risk assessment
3.
4. Metabolism is the sum of biochemical changes
Anabolism is the sum of biochemical changes that “build up” complex molecules
Catabolism is the sum of biochemical changes that “break down” complex
molecules.
The human body has the capacity to eliminate
most toxicants either in their original chemical
form or as a metabolite
5. Biotransformation
is the process by which both
endogenous and exogenous
substances that enter the body are
changed from hydrophobic to
hydrophilic molecules to facilitate
elimination from the body.
6. Hemoglobin is metabolized to
bilirubin
Bilirubin is toxic to the brain of
newborns
Liver biotransforms the lipophilic
bilirubin molecule in to water-
soluble (hydrophilic) metabolite.
7. Biotransformation produces four
changes
altered toxicant molecules, are
chemically distinct from the
original toxicant
metabolites are usually more
hydrophilic
than the original toxicant
8. the hydrophilic nature of the
biotransformed
metabolites reduces their ability to
cross
membranes
reduced reabsorption of
metabolites by cells associated
with the organs of elimination
(kidneys and intestines).
9. The biological half-life (T½)
is the time required to reduce by
half the quantity of a toxicant
present in the body (e.g., plasma).
10. Two types of reactions
phase I reactions
phase II reactions
11. The goal of the phase I and phase II
biotransformation reactions is to facilitate
detoxification
13. The first pass means that blood
from the gastrointestinal tract is
shunted directly to the
liver via the portal vein
The liver removes potentially toxic
chemicals from the blood prior to
distribution
The liver’s biotransformation
capacity
is not specific for toxicants
14.
15. the enzymes that catalyze
biotransformation reactions in
hepatocytes and in other cells in
the body occur
free in the cytoplasm or
bound to the membrane of the
endoplasmic reticulum.
16. Microsomal enzymes are
membrane bounded
in the form of vesicles
associated with phase I reactions.
17. Cytosolic enzymes are
non-membrane bound
occur free within the cytoplasm.
associated with phase II reactions.
18. During phase I biotransformation
reactions
a small polar group is exposed on
the toxicant or added to the
toxicant.
the polar group enhances the
solubility of the toxicant in water,
which favors elimination.
19. The reactions are catalyzed by
nonspecific enzyme systems, the
most important of which is
cytochrome P-450.
Cytochromes are iron—protein
complexes that transport electrons
(or hydrogen) by
changing the valency of iron (e.g.,
Fe++→
Fe++++e- or Fe+++ +e-→Fe++).
20. Phase I reactions usually involve:
oxidation
which occurs when the toxicant
loses electrons,
reduction
when the toxicant gains electrons
21. hydrolysis,
a process that cleaves (splits)
the toxicant into two or more
simpler
molecules, each of which then
combines
with a part of water (i.e., H+ and
OH-) at
the site of cleavage.
22.
23. Phase I biotransformation
will result in metabolites
sufficiently ionized, or hydrophilic,
to be either readily eliminated
from the body without further
biotransformation reactions
required
or rendered as an intermediate
metabolite ready for phase II
biotransformation.
24. Phase II reactions are referred to as
conjugation reactions.
These reactions produce a
conjugate metabolite that is more
water-soluble than the original
toxicant or phase I metabolite.
25. In most instances the hydrophilic
phase II
metabolite can be readily
eliminated from
the body
26. Glucuronidation
the process of adding glucuronide to the toxicant or phase I metabolite.
Sulfate conjugation
the highly polar sulfate conjugates are readily secreted in urine.
27. Other phase II reactions may
involve the addition of a methyl
group (-CH3) or an amino acid,
most commonly glycine
29. Hughes, W. William. 2005. Essentials of environmental toxicology: The Effects of Environmentally
Hazardous Substances on Human Health. Taylor & Francis, 325 Chestnut St., Suite 800,
Philadelphia, Pa 19106. pp. 71-78
Shaw, I. and J. Chadwick. 2002. Principles of Environmental Toxicology. Taylor & Francis Ltd, 1
Gunpowder Square, London EC4A 3DF.
Yu, Ming-Ho. 2005. Environmental toxicology: biological and health effects of pollutants. 2nd
edition. CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431
Editor's Notes
Biotransformation is responsible for changing naturally occurring lipophilic molecules into hydrophilic metabolites that are more readily eliminated from the body
A good example of biotransformation is the fate of hemoglobin,the oxygen-carrying iron—protein complex in red blood cells. Under normal conditions hemoglobin is metabolized to bilirubin, one of a number of hemoglobin metabolites. Bilirubin is toxic to the brain of newborns and, if present in high concentrations, may cause irreversible brain injury. Biotransformation of the lipophilic bilirubin molecule in the liver results in the production of a water-soluble (hydrophilic) metabolite excreted into bile and eliminated via feces.
The biological half-life provides a means for comparing the residence times for different toxicants in the body. This information is useful when establishing “safe” exposure durations for toxicants.
The chemical reactions responsible for changing a lipophilic toxicant into a chemical form which the body can eliminate are termed phase I and phase II biotransformations
Detoxification, thus producing water-soluble metabolites that are more readily eliminated by the urinary and biliary (pertaining to liver bile) systems.
The liver receives blood directly from the gastrointestinal tract, where chemicals, nutrients, and toxicants are absorbed. Blood, with its gastrointestinally derived “chemical payload,” is eventually distributed to all other tissues.
The liver uses phase I and phase II biotransformation reactions that, in addition to the “normal” work of biotransforming endogenous chemicals (e.g., bilirubin) and xenobiotics, are also capable of chemically modifying
toxicants to facilitate their elimination from the body.
The term microsomal describes the “small bodies” or vesicles that form when hepatocytes or liver tissue is homogenized (blended) to form an acellular homogenate (pureed hepatocytes!). Within the homogenate, small segments of endoplasmic reticulum membranes with bound phase I enzymes spontaneously form small
vesicles.
Cytochrome P-450 gets it name from the observation that, in its reduced state (i.e., Fe++), this iron—protein complex has a maximum absorbance of visible light at 450 nm (1nanometer = 10–9 meters; the part of the
spectrum that is visible to the human eye ranges from violet at 390 nm to red at 760 nm).
On completion of a phase I reaction, the new intermediate metabolite produced contains a reactive chemical group (e.g., hydroxyl, -OH; amino, -NH2; or carboxyl, -COOH). For many intermediate metabolites the reactive sites, which were either exposed or added during phase I biotransformation, do not confer sufficient hydrophilic properties to permit elimination from the body. These metabolites must undergo additional biotransformation,
called a phase II reaction.
The resulting glucuronic acid conjugate is excreted into the bile, which then moves on to the intestine for elimination in the feces.Typically, glucuronic acid conjugates with MW> 350 are secreted in the bile, while those with MW<250 are secreted by the kidney.
.
In other phase II reactions Sodium salicylate (aspirin) is eliminated as a glycine—salicylic acid conjugate in the urine
