The two phases in the biotransformation of lipophilic naphthalene. Biotransformation of xenobiotics pharmacology 23,286 views enzymatic modification of the drug occurring within the living organisms or chemical transformation a drug goes through in living organisms or biological fluids is known as biotransformation. In general, these conjugates are more soluble in water and more readily excretable. The main evolutionary goal of biotransformation is to increase the rate of excretion of xenobiotics or drugs. A low capacity exists in the skin, intestines, testes, and placenta. Functional medicine universitys functional diagnostic medicine training program module 6. Transferases cytosolic or bound in membranes of er catalyze. Basic concepts 5 phase ii reactions involves the binding of molecules to either the original toxic molecule or the toxic molecule metabolite derived from the phase i reactions. Chapter 6 biotransformation of xenobiotics flashcards. Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more watersoluble compounds. Induction of phase i, ii and iii drug metabolismtransport by. In general, biotransformation reactions are divided into two broad. This work is licensed under a creative commons attribution.
Metabolic biotransformation of xenobiotics mammalian. These compounds are then subjected to phase ii reactions, also known as. Phase i of biotransformation is mediated by inducible cytochrome p450 dependent. Since the liver is the primary site for biotransformation, it is also potentially vulnerable to the toxic action of a xenobiotic that is activated to a more toxic compound. In addition to hydroxylation, a wide range of reactions also take place including deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction 6. Xenobioticmetabolizing enzymes can be divided into phase i, phase ii, and transporter enzymes. Phase ii drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologically active compounds. This chapter focuses on phase ii biotransformation reactions also called. More generally, xenobiotic metabolism from the greek xenos stranger and biotic. May 18, 2016 phase 2 biotransformation reaction animated biology with arpan. Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more watersoluble compounds xenobiotic biotransformation is accomplished by a limited number of enzymes.
Phase i metabolites if not readily excretable or contain component ends, combine with endogenous substrates like glucuronic acid, sulphuric acid, amino acid or acetic acid, to undergo conjugation reactions, yielding more excretable drug conjugates which are excreted by the kidneys. Reactions of biotransformation phase ii the reactions render xenobiotics even more watersoluble enabling excretion of them into the urine or bile, convert the biologically active products of phase i. In contrast with phase i enzymes biotransformation, phase ii conjugating enzymes have received less attention. Liver and biotransformation of xenobiotics functions.
Metabolism of xenobiotics metabolism of xenobiotics. Involves the complexing or conjugation of xenobiotics with relatively large and. The final product is usually water soluble and, therefore, easier to excrete from the body. What are the differences between these two phases of drug biotransformationmetabolism. Many phase i metabolites are not sufficiently polar to be directly excreted by the kidneys. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Xenobiotics, biotransformation, drug synergism and the. Phase ii drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic.
Biotransformation is the process by which a xenobiotics is chemically altered by the body. Conjugative phase ii dmes include uridine 5 diphospho udp glucuronosyltransferase s ugt s, sulfotransferase s sults, glutathione s transferase s gsts, n acetyltransferase s nats, and methyl. Nov 23, 2012 metabolism of xenobiotics metabolism of xenobiotics occurs in two phases phase 1, the major reaction involved is hydroxylation. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. This page provides homology modeled 3d structures of all enzymes figure 1e. To make use of a compound or to facilitate its excretion. Phase ii reactions include glucuronidation, sulfation, acetylation.
As illustrated in figure 5, benzene is biotransformed initially to phenol by a phase i reaction oxidation. The liver has enzymes that facilitate chemical reactions such as oxidation, reduction, and hydrolysis of xenobiotics phase i. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to slightly increase hydrophilicity. This chapter addresses the phase ii biotransformation reactions that a drug or. Phase i reactions n, o, sdealkylation n, s, poxidation oxidative deamination phase ii reactions conjugation reactions the addition of polar groups carbohydrate derivatives, amino acids. Edward croom, in progress in molecular biology and translational science, 2012. Chapter 6 biotransformation of xenobiotics flashcards quizlet. Conjugation, role, fate of products, description and examples.
Phase i reactions introduce polar groups into the chemical, including carboxyl, epoxide, hydroxyl, sulfhydryl, amine, hydroxylamine, and imine. Phase 2 biotransformation reaction animated biology with arpan. The pointless attachment to phase i and phase ii classification structure. In phase i, enzymes such as cytochrome p450 oxidases introduce reactive or polar groups into xenobiotics.
Ii biotransformation of xenobiotics and hormones osmo hanninen encyclopedia of life support systems eolss spring, which was translated into many. Drug metabolizing enzymes and biotransformation reactions 1 nalia at penner, caoline r woodward and, chandra prakash a. Phase ii reactions enzymatic reactions that result in the conjugation of large watersoluble, charged polarbiomolecules to xenobiotics for these reactions to occur, a functional group must be present on either the parent compound or its phase i product. Biotransformation is the chemical modification or modifications made by an organism on a chemical compound. The biotransformation of benzene requires both phase i and phase ii reactions. Choose from 26 different sets of biotransformation xenobiotic flashcards on quizlet. On top of that, biotransformation can occur when drugs undergo further metabolic steps following conjugation, including things like covalent binding to dna and proteins. Due to the biotransformation, the molecular structure of a drug is commonly changed to be more hydrophilic and the substances can be readily eliminated from the body 2.
Possible utilization of some phase ii enzymes biotransformation for xenobiotic. A vicious takedown of the phase i phase ii classification system is available from josephy et al 2005. Reactions of biotransformation phase ii the reactions render xenobiotics even more watersoluble enabling excretion of them into the urine or bile, convert the biologically active products of phase i reactions into less active or inactive species. The role of biotransformation in the estrogenicity of xenobiotics. Biotransformation of organic xenobiotics normally proceed in a first step of oxidation phase i that introduces a reactive group in the xenobiotic, and a. Examples of each type of conjugation have been illustrated below. Induction of phase i, ii and iii drug metabolismtransport. First biotransformation phase biotransformation itself in the first phase new functional groups are inserted to the molecule of xenobiotic. Currently, data from in vivo preclinical and in vitro human tissue studies are used in predicting the safety and human pharmacokinetics, and assessing the potential of a new chemical entity nce as a successful. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups.
Biotransformation of xenobiotics pharmacology 23,286 views enzymatic modification of the drug occurring within the living organisms or chemical transformation a drug goes through in living. These reactions expose or introduce a functional group oh, nh 2, sh, or cooh, and usually result in only a small increase in hydrophilicity. Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities. Or, one may instead make use of parkinson and ogilvies biotransformation of xenobiotics, a chapter probably from casarett and doulls toxicology. The metabolic biotransformation reactions of xenobiotics encompasses changes in these chemicals produced by biological environments. Although phase i drug metabolism occurs in most tissues.
Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions. Mar 31, 2020 however, if you are among those that have been searching for answers to phase 2 metabolism reactions, phase 1 and phase 2 reactions in drug metabolism ppt, lecture notes on xenobiotics, xenobiotic metabolism ppt, xenobiotic metabolism pdf, induction of phase i ii and iii drug metabolism transport by xenobiotics, phase 1 reactions biotransformation, drug metabolism liver, xenobiotics. Lipophilic xenobiotics are often first metabolized by phase i enzymes, which function to make xenobiotics more polar and provide sites for conjugation reactions. The liver is the principal, but not the only, site of xenobiotics biotransformation.
Biotransformation of organic xenobiotics normally proceed in a first step of oxidation phase i that introduces a reactive group in the xenobiotic, and a second step of conjugation phase ii with a nontoxic endogenous metabolite that yields an excretable product. Phase ii reactions involve several types of endogenous metabolites that may form conjugates with the xenobiotics or their metabolites. Xenobiotics are unwanted chemicals in the environment and the diet that the body is exposed to. In the first phase the oxidation by cytochrome p450 introduces a hydroxyl group and in the. Biotransformation means chemical alteration of chemicals such as nutrients, amino acids, toxins, and. Phase ii biotransformation reactions include glucuronidation, sulfonation more commonly called sulfation, acetylation, methylation, and conjugation with. Biotransformation of xenobiotics and hormones eolss.
To make use of a compound or to facilitate its excretion increases the. Oglucuronidation of phenolic drugs or other xenobiotics is often in. To find drugs that are metabolized by specific phase i, phase ii or transporter enzymes, users can perform a search by clicking on biotransformation. Mar 16, 2014 what are the differences between these two phases of drug biotransformation metabolism.
Polar xenobiotics are easily eliminated by the body through urine, sweat, etc. In addition to hydroxylation, a wide range of reactions also. Activate naturalendogenous compounds for normal function. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Phase ii reactions enzymatic reactions that result in the conjugation of large watersoluble, charged polarbiomolecules to xenobiotics for these reactions to occur, a. Phase i and phase ii biotransformation reactions deranged. The biotransformed metabolite is more toxic than the original compound. Start studying chapter 6 biotransformation of xenobiotics. The physiology and biochemistry of biotransformation. Introduction of phase i, phase ii drug metabolizing enzymes and phase iii drug transporters drug metabolizing enzymes dmes play central roles in the metabolism, elimination andor detoxification of xenobiotics or exogenous compounds introduced into the body meyer, 1996.
However, if you are among those that have been searching for answers to phase 2 metabolism reactions, phase 1 and phase 2 reactions in drug metabolism ppt, lecture notes on xenobiotics, xenobiotic metabolism ppt, xenobiotic metabolism pdf. Phase i reactions involve hydrolysis, reduction, and oxidation. To make use of a compound or to facilitate its excretion increases the water solubility of a compound divided in two phases, phase i and phase ii. Biotransformation of xenobiotics linkedin slideshare.
Unlike other phase ii reactions, acetylation masks an amine with a nonionizable group and are less water soluble than the parent compound. These modified compounds are then conjugated to polar compounds in phase ii reactions. Liver is the second largest organ in the body the largest is skin, weighing approximately 1,5 kg. These reactions are catalysed by transferase enzymes such as glutathione stransferases. Overview major phase i and phase ii enzymes reaction mechanisms, substrates. Metabolism of xenobiotics metabolism of xenobiotics occurs in two phases phase 1, the major reaction involved is hydroxylation. Biotransformation reactions grouped as phase i functional group modification and phase ii conjugation. Ii biotransformation of xenobiotics and hormones osmo hanninen encyclopedia of life support systems eolss spring, which was translated into many languages draw the attention of great public on the environmental problems caused by the chemicals spread for various purposes in nature. Biotransformation changes the properties of a xenobiotic usually from a lipophilic form that favors absorption to a hydrophilic form favoring excretion in the urine or bile. Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal. Introduction of phase i, phase ii drug metabolizing enzymes and phase iii drug transporters drug metabolizing enzymes dmes play central roles in the metabolism, elimination. Biotransformation can detoxify or bioactivate xenobiotics to. Overview major phase i and phase ii enzymes reaction mechanisms, substrates enzyme inhibitors and inducers genetic polymorphism detoxification metabolic activation fda guidances related to biotransformation.
However, lipophilic xenobiotics require a sophisticated. The overall purpose of the two phases of metabolism of xenobiotics is to increase their water solubility. Biotransformation an overview sciencedirect topics. Humans are exposed daily to a wide variety of foreign compounds called xenobioticssubstances absorbed across. This page provides homology modeled 3d structures of all enzymes figure 1 e. Nacetylation of xenobiotics is performed by nacetyltransferases nat nacetylation is a major route of biotransformation for xenobiotics containing an aromatic amine rnh2. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Biotransformation includes chemical modification of the xenobiotic by oxidation. Phenol has a structure including a functional hydroxyl group that is then conjugated by a phase ii reaction sulfation to phenyl sulfate.
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