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nutritional aspects of biotransformation
1. NUTRITIONAL ASPECTS
OF
BIOTRANSFORMATION
Ms. Latika Yadav (Research Scholar), Dept. of Foods and Nutrition,
College of H.Sc,Maharana Pratap University of Agriculture and
Technology, MPUAT, Udaipur, rajasthan-313001, email.id:
a.lata27@gmail.com
2. INTRODUCTION
Biotransformation is the chemical modification (or
modifications) made by an organism on a chemical
compound. If this modification ends in mineral compounds
like CO2, NH4+, or H2O, the biotransformation is
called mineralisation.
Biotransformation means chemical alteration of chemicals
such as (but not limited to) nutrients, amino acids, toxins, and
drugs in the body. It is also needed to render nonpolar
compounds polar so that they are not reabsorbed in renal
tubules and are excreted. Biotransformation of xenobiotics
can dominate toxicokinetics and the metabolites may reach
higher concentrations in organisms than their parent
compounds.
Biotransformation of Xenobiotics
Biological basis for xenobiotic metabolism:
To convert lipid-soluble, non-polar, non-excretable
forms of chemicals to water-soluble, polar forms that are
excretable in bile and urine
3. Exposure to a variety of chemicals, including food additives, drugs, insecticides,
industrial chemicals, and pollutants collectively called xenobiotics ( from
Greek: xenos, foreign; bios, life).
The primary purpose of detoxication is to convert toxic substances into polar
compounds, which are thus less lipid soluble. The object is to decrease
permeability of the compound through the lipid membranes, thus protecting the
cell interior, and also to increase the water solubility and hence the excretion of
the compound from the body via the urine or bile depending on molecular size.
The detoxication process decreases or abolishes the toxicity of the compound.
however, the detoxified products are more toxic than the parent compounds.
Therefore, biotransformation is the term commonly used for the process that
involves not only a reduction in toxicity but also an increase in toxicity.
4. The Truck-Hitch-Trailer Analogy to Xenobiotic Biotransformation
Foreign Chemical
(xenobiotic)
TRUCK
•lipophilic
•not charged
•not water soluble
•poorly excretable
7. •Many xenobiotics undergo chemical transformation (biotransformation;
metabolism) when introduced into biologic systems like the human body.
•Biotransformation is often mediated by enzymes
•End result of biotransformation is either alteration of the parent molecule,
or conjugation of the parent molecule (or its metabolites) with endogenous
substances in the body.
•Enzymes involved in biotransformation can act on either endogenous or
xenobiotic compounds, especially if the xenobiotics are structurally similar
to endogenous compounds
•The products of biotransformation can be either less toxic, more toxic, or
about as toxic as the parent molecules.
•Enzymes involved in biotransformation are sometimes called “drug
metabolizing enzymes”. Although strictly speaking this is a misnomer
because many of the substrates are not drugs, the term is still commonly
used.
8. DETOXICATION PROCESS
The chemical reactions of
enzymatic biotransformation are
classified as Phase I and Phase
II reactions
Phase I reactions convert the
parent compound to polar
metabolite by oxidation,
reduction, or hydrolysis. The
resulting metabolite may be
nontoxic, less toxic, or
occasionally more toxic than the
parent compound.
Phase II reactions involve the
coupling of the parent substance
or its metabolite with an The net result of phase I and phase II
endogenous substrate such as reactions is to greatly decrease the toxicity
glucuronate, glycine, or and increase the excreatibility of toxic
glutathione. substances.
9. Biotransformation Enzyme- Containing Cells in Various Organs
organs Cell(s)
Liver Parenchymal cells (hepatocytes)
Kidney Proximal tubular cells (S3 segment)
Lung Clara cells, Type II alveolar cells
Intestine Mucosa lining cells
Skin Epithelial cells
10. Major Biotransformation Reactions
Phase I Phase II
1.Oxidation 1.Sulfation
2.Reduction 2.Glucuronidation
3.Hydrolysis 3.Acetylation
4.Methylation
5.Glutathione conjugation
11. PHASE I REACTIONS
1. OXIDATION
The oxidation of xenobiotics is achieved either by the removal of hydrogen or the
addition of oxygen.
There are enzymes that catalyze the oxidation of a variety of aliphatic alcohols.
Alcohol dehydrogenase, which present in liver cytosol, in the presence of nicotinamide
adenine dinucleotide (NAD) catalyzes the
Ethyl alcohol + NAD Acetaldehyde + NADH
Acetaldehyde dehydrogenase converts acetyldehyde in the presence of NAD to acetic
acid which can be further oxidized to carbon di oxide and water or can be used for
the synthesis of physiological compounds.
Monoamine oxidase (MAO), a mitochondrial enzyme found in all tissues except
erythrocytes, oxidatively deaminates both endogeneous amines ( epinephrine,
norepinephrine and serotonin) and exogeneous amines to their corresponding aldehydes
MAO has an important protective function in coping with our chemical environment
such as metabolism of tyramine that is present in cheese and some other food.
12. The most important enzyme systems involved in phase I reactions are the
Cytochrome P450 containing monooxygenases, also called mixed
function oxidases (MFOs), which are localized in the hepatic endoplasmic
reticulum.
This system is composed of two enzymes:
1. a heme protein called cytochrome P450 and
2. a flavin enzymes called Cytochrome P450 reductase.
The enzyme system requires NADPH and molecular oxygen.
The enzymes are present in all mammalian cell types except mature red blood
cells and skeletal muscle cells.
The liver has the highest concentration of total cytochrome P450
concentration of any organ and is thus the main site of XENOBIOTIC
metabolism.
13. 2. Reduction
Enzymes in the endoplasmic reticulum and cytosol of the liver and other
tissues can catalyse these reduction:
•Azo reduction – reduction of an azo bond (N=N) to two amines
(NH2)
•Nitro reduction – reduction of a nitro group (NO2) to an amine
e.g. transformation of inactive form of drug ( prontosil) to the active
form
( sulfanilamide).
3. Hydrolysis
Liver and other tissues contain a number of nonspecific esterases and
amidases that can hydrolyze ester and amide linkages in foreign
compounds
• Addition of water (H2O) to an ester bond (CO-O-C) to form an
alcohol (C-OH) and a carboxylic acid (COOH)
e.g. Aspirin ( acetylsalicylic acid) undergoes hydrolysis, forming
acetate and salicylic acid. Acetate is either oxidized or used for the
synthesis of physiological compounds, and salicylic acid is
excreted as such or in conjugated form by the kidney.
14. Phase II reactions
Involve addition of a cofactor to a substrate to form a new
product. Therefore, the rate of these reactions can be limited by the
availability of the cofactor.
Phase II enzymes may be either microsomal or cytosolic. This is
because the primary purpose of the Phase II reactions is not so much
to increase the polarity of the parent compound (although that is part
of what they accomplish). The primary purpose is to increase the
molecular weight of the parent compound to make it a better
substrate for active transport mechanisms in the biliary tract.
Various factors can affect the availability of cofactors. For example,
fasting markedly reduces the amount of glutathione available in the
liver.
15. 1. Sulfation
• Replacement of a hydrogen atom (H) with a sulfonate (SO3-)
• Uses the enzyme sulfotransferase
• Uses the cofactor called PAPS (phosphoadenosine phosphosulfate)
• Produces a highly water-soluble sulfuric acid ester.
16. 2. Glucuronidation
• Replacement of a hydrogen atom with a glucuronic acid
• Uses the enzyme UDP-glucuronosyl transferase (UDP-GT)
• Uses the cofactor called UDPGA (uridine diphosphate glucuronic acid)
• One of the major Phase II enzymatic pathways
Example: Conjugation of a phenol and a carboxylic acid with glucuronic
acid
3. Acetylation
• Replacement of a hydrogen atom with an acetyl group
• Uses the enzyme acetyltransferase
• Uses the cofactor called acetyl CoA (acetyl coenzyme A)
• Sometimes results in a less water-soluble product
17. 4. Methylation
•Replacement of a hydrogen atom with a methyl group
•Uses the enzyme methyltransferase
•Uses the cofactor called SAM (S-adenosyl methionine)
•Common but relatively minor pathway
5.Glutathione conjugation
• Adds a glutathione molecule to the parent compound, either by direct
addition or by replacement of an electrophilic substituent (e.g., a
halogen atom)
• Uses the enzyme glutathione transferase (GST)
• Uses the cofactor called glutathione (a tripeptide made up of glycine,
cysteine, and glutamic acid
• One of the major Phase II enzymatic pathways
18. Significance of Biotransformation Reactions in Toxicology
• Biotransformation is a major part of the pathway for
elimination of many xenobiotic compounds.
• Biotransformation can result in either a decrease or an increase
(or no change) in toxicity.
• Biotransformation can result in the formation of reactive
metabolites.
19. Factors affecting xenobiotic metabolism
1. Age: The metabolizing enzymes in neonates are not fully developed,
therefore those cannot efficiently metabolize drugs. Also in the elderly,
enzymatic systems may not function well leading to same conclusion.
2. Sex: Males who are deficient in glucose -6-phosphate dehydrogenase
are more prone to hemolysis when subjected to some drugs like
sulfonamides.
3. Pregnancy: Hepatic metabolism of drugs is decreased in pregnancy.
4. Nutritional status/ liver dysfunction: Malnutrition can cause a
decreased level of some enzyme system and liver dysfunction can lead
to decreased metabolism
5. Bioactivation: Some drugs may be transformed to more toxic
metabolites
6. Enzyme induction / inhibition: A result of this is either an increase in
the metabolism or a decrease in the drug metabolism.
7. Changes in the kinetic mechanism: depending on whether the
concentration of drug is in the therapeutic or overdose range.
