A low capacity exists in the skin, intestines, testes, and placenta. Polar xenobiotics are easily eliminated by the body through urine, sweat, etc. These compounds are then subjected to phase ii reactions, also known as. Humans are exposed daily to a wide variety of foreign compounds called xenobioticssubstances absorbed across. 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. 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. Phase i reactions involve hydrolysis, reduction, and oxidation. Metabolic biotransformation of xenobiotics mammalian. 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. Functional medicine universitys functional diagnostic medicine training program module 6. Phase 2 biotransformation reaction animated biology with arpan.
This work is licensed under a creative commons attribution. The biotransformed metabolite is more toxic than the original compound. First biotransformation phase biotransformation itself in the first phase new functional groups are inserted to the molecule of xenobiotic. Biotransformation of xenobiotics and hormones eolss. In addition to hydroxylation, a wide range of reactions also. Biotransformation of xenobiotics linkedin slideshare. Liver is the second largest organ in the body the largest is skin, weighing approximately 1,5 kg. Biotransformation means chemical alteration of chemicals such as nutrients, amino acids, toxins, and. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions.
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. The main evolutionary goal of biotransformation is to increase the rate of excretion of xenobiotics or drugs. Metabolism of xenobiotics metabolism of xenobiotics occurs in two phases phase 1, the major reaction involved is hydroxylation. The physiology and biochemistry of biotransformation. Biotransformation is the chemical modification or modifications made by an organism on a chemical compound. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. 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. Induction of phase i, ii and iii drug metabolismtransport. Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities.
Lipophilic xenobiotics are often first metabolized by phase i enzymes, which function to make xenobiotics more polar and provide sites for conjugation reactions. 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. Phase ii reactions involve several types of endogenous metabolites that may form conjugates with the xenobiotics or their metabolites. A vicious takedown of the phase i phase ii classification system is available from josephy et al 2005. This page provides homology modeled 3d structures of all enzymes figure 1 e. In general, biotransformation reactions are divided into two broad. Liver and biotransformation of xenobiotics functions. As illustrated in figure 5, benzene is biotransformed initially to phenol by a phase i reaction oxidation. Biotransformation can detoxify or bioactivate xenobiotics to. The pointless attachment to phase i and phase ii classification structure. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound.
Xenobiotics are unwanted chemicals in the environment and the diet that the body is exposed to. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Oglucuronidation of phenolic drugs or other xenobiotics is often in. Drug metabolizing enzymes and biotransformation reactions 1 nalia at penner, caoline r woodward and, chandra prakash a. The metabolic biotransformation reactions of xenobiotics encompasses changes in these chemicals produced by biological environments. Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more watersoluble compounds xenobiotic biotransformation is accomplished by a limited number of enzymes. This chapter addresses the phase ii biotransformation reactions that a drug or. Phase i reactions introduce polar groups into the chemical, including carboxyl, epoxide, hydroxyl, sulfhydryl, amine, hydroxylamine, and imine. These modified compounds are then conjugated to polar compounds in phase ii reactions. 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. To make use of a compound or to facilitate its excretion. 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 ii biotransformation reactions include glucuronidation, sulfonation more commonly called sulfation, acetylation, methylation, and conjugation with.
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. The overall purpose of the two phases of metabolism of xenobiotics is to increase their water solubility. 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. Phase i and phase ii biotransformation reactions deranged. This page provides homology modeled 3d structures of all enzymes figure 1e. Mar 16, 2014 what are the differences between these two phases of drug biotransformation metabolism. What are the differences between these two phases of drug biotransformationmetabolism.
To find drugs that are metabolized by specific phase i, phase ii or transporter enzymes, users can perform a search by clicking on biotransformation. The biotransformation of benzene requires both phase i and phase ii reactions. Unlike other phase ii reactions, acetylation masks an amine with a nonionizable group and are less water soluble than the parent compound. 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. The two phases in the biotransformation of lipophilic naphthalene.
Xenobioticmetabolizing enzymes can be divided into phase i, phase ii, and transporter enzymes. Biotransformation of organic xenobiotics normally proceed in a first step of oxidation phase i that introduces a reactive group in the xenobiotic, and a. Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal. The liver has enzymes that facilitate chemical reactions such as oxidation, reduction, and hydrolysis of xenobiotics phase i. 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. Induction of phase i, ii and iii drug metabolismtransport by. In addition to hydroxylation, a wide range of reactions also take place including deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction 6. 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 of biotransformation is mediated by inducible cytochrome p450 dependent. Chapter 6 biotransformation of xenobiotics flashcards.
Conjugation, role, fate of products, description and examples. Many phase i metabolites are not sufficiently polar to be directly excreted by the kidneys. However, lipophilic xenobiotics require a sophisticated. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. 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. In the first phase the oxidation by cytochrome p450 introduces a hydroxyl group and in the. Transferases cytosolic or bound in membranes of er catalyze. To make use of a compound or to facilitate its excretion increases the. The final product is usually water soluble and, therefore, easier to excrete from the body. More generally, xenobiotic metabolism from the greek xenos stranger and biotic. 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. Metabolism of xenobiotics metabolism of xenobiotics. Although phase i drug metabolism occurs in most tissues. These reactions are catalysed by transferase enzymes such as glutathione stransferases.
Edward croom, in progress in molecular biology and translational science, 2012. In phase i, enzymes such as cytochrome p450 oxidases introduce reactive or polar groups into xenobiotics. Biotransformation an overview sciencedirect topics. These reactions expose or introduce a functional group oh, nh 2, sh, or cooh, and usually result in only a small increase in hydrophilicity. 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. Or, one may instead make use of parkinson and ogilvies biotransformation of xenobiotics, a chapter probably from casarett and doulls toxicology. Biotransformation is the process by which a xenobiotics is chemically altered by the body.
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 ii reactions include glucuronidation, sulfation, acetylation. 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. 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. Ii biotransformation of xenobiotics and hormones osmo hanninen encyclopedia of life support systems eolss spring, which was translated into many. Reduced metabolising capacity of phase ii enzymes can lead to toxic effects of clinically used drugs. Xenobiotics, biotransformation, drug synergism and the. In general, these conjugates are more soluble in water and more readily excretable. 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. Activate naturalendogenous compounds for normal function.
Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more watersoluble compounds. Chapter 6 biotransformation of xenobiotics flashcards quizlet. 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. Involves the complexing or conjugation of xenobiotics with relatively large and. On top of that, biotransformation can occur when drugs undergo further metabolic steps following conjugation, including things like covalent binding to dna and proteins. The liver is the principal, but not the only, site of xenobiotics biotransformation. Possible utilization of some phase ii enzymes biotransformation for xenobiotic. Nov 23, 2012 metabolism of xenobiotics metabolism of xenobiotics occurs in two phases phase 1, the major reaction involved is hydroxylation. This chapter focuses on phase ii biotransformation reactions also called. Choose from 26 different sets of biotransformation xenobiotic flashcards on quizlet. 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 reactions grouped as phase i functional group modification and phase ii conjugation. Start studying chapter 6 biotransformation of xenobiotics.
May 18, 2016 phase 2 biotransformation reaction animated biology with arpan. Overview major phase i and phase ii enzymes reaction mechanisms, substrates. Phenol has a structure including a functional hydroxyl group that is then conjugated by a phase ii reaction sulfation to phenyl sulfate. Examples of each type of conjugation have been illustrated below. In contrast with phase i enzymes biotransformation, phase ii conjugating enzymes have received less attention. The role of biotransformation in the estrogenicity of xenobiotics.
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. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to slightly increase hydrophilicity. Biotransformation includes chemical modification of the xenobiotic by oxidation. 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.1186 1336 59 1472 1340 1325 1526 1063 1458 1485 1179 907 208 1228 1 37 153 713 1089 674 1462 146 769 28 1366 148 833 360 1094 116 911 232 1001 829 1015 1106 1228 597