nutritional aspects of biotransformationPresentation Transcript
NUTRITIONAL ASPECTS OF BIOTRANSFORMATIONMs. 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: email@example.com
INTRODUCTIONBiotransformation 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 XenobioticsBiological 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
Exposure to a variety of chemicals, including food additives, drugs, insecticides, industrial chemicals, and pollutants collectively called xenobiotics ( fromGreek: 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.
The Truck-Hitch-Trailer Analogy to Xenobiotic Biotransformation Foreign Chemical (xenobiotic) TRUCK •lipophilic •not charged •not water soluble •poorly excretable
The Truck-Hitch-Trailer Analogy to Xenobiotic Biotransformation
The Truck-Hitch-Trailer Analogy to Xenobiotic Biotransformation
•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.
DETOXICATION PROCESSThe chemical reactions ofenzymatic biotransformation areclassified as Phase I and PhaseII reactionsPhase I reactions convert theparent compound to polarmetabolite by oxidation,reduction, or hydrolysis. Theresulting metabolite may benontoxic, less toxic, oroccasionally more toxic than theparent compound.Phase II reactions involve thecoupling of the parent substanceor its metabolite with an The net result of phase I and phase IIendogenous substrate such as reactions is to greatly decrease the toxicityglucuronate, glycine, or and increase the excreatibility of toxicglutathione. substances.
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
Major Biotransformation Reactions Phase I Phase II1.Oxidation 1.Sulfation2.Reduction 2.Glucuronidation3.Hydrolysis 3.Acetylation 4.Methylation 5.Glutathione conjugation
PHASE I REACTIONS 1. OXIDATIONThe 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 + NADHAcetaldehyde 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 aldehydesMAO 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.
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.
2. ReductionEnzymes 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. HydrolysisLiver 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.
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.
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.
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
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 pathway5.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
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.
Factors affecting xenobiotic metabolism1. 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 metabolism5. Bioactivation: Some drugs may be transformed to more toxic metabolites6. 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.
REFERENCES 1. www.healthadviceonline2. S.Vishwanathan, 2012, “Nutritional aspect of biotransformation”, clinical nutrition,p553:565,CRC Press.3. Text book of Biopharmaceutics & pharmacokinetics, Dr.Sobha Rani R. Hiremath, Prism Books Pvt Ltd, Bangalore, 2000 Pg.no. 157-166.4. www.pharmacology.com