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. Phase ii reactions involve several types of endogenous metabolites that may form conjugates with the xenobiotics or their metabolites. Reactions of functionalization comprise oxidations electron removal, dehydrogenation, and oxygenation, reductions electron addition, hydrogenation, and removal of oxygen, and hydrationsdehydrations hydrolysis and addition or removal of water. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. These reactions expose or introduce a functional group oh, nh 2, sh, or cooh, and usually result in only a. The most important enzyme system involved in phase i reactions are the cytochromes p450, also called the cytochrome p450 system or the mixed function oxidase mfo system, but now mostly called cyp450 or cyps by scientists and in research publications. Distinguish between phase i and phase ii reactions. Phase 1 andor phase 2 some drugs undergo either phase 1 or phase 2 metabolism, but most undergo phase 1. Biotransformation pathways drug metabolism reactions have been divided into two classes. Basic concepts 4 interaction with these enzymes may change the toxicant to either a less or a more toxic form. Metabolites of many drugs undergo phase ii metabolism. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for electron transfer to cytochrome p450 in the microsome of the. Functional medicine universitys functional diagnostic medicine training program module 6. Phase i reactions, also known as functionalization reactions, involve the transformation of lipophilic drugs into a more watersoluble compound.
Be able to distinguish enzymes and why each phase is important. Normally phase i reactions are followed by phase ii reactions but in case of isoniazid antituberculous drug, phase ii reactions occur before phase i reactions because nacetyl moiety acts as an endogenous substrate for the conjugation reaction. Biotransformation reactions take place mainly in the liver hepatic. Phase i involves catabolic reactions that break down the toxicant into various components. Petra jancovaa, pavel anzenbacherb eva anzenbacherova. Phase ii biotransform of drugs linkedin slideshare. 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.
Unlike p450, phase ii reactions are concerted reactions that involve an electrophile y, a nucleophile x and a leaving group l these reactions involve a pair of electrons, i. Biotransformation reactions grouped as phase i functional group modification and phase ii conjugation. A small polar group is either exposed on the toxicant or added to the toxicant oxidation reduction hydrolysis acetylation 6. This work is licensed under a creative commons attribution. In general, biotransformation reactions are divided into two broad categories known as phase i and phase ii reaction.
Drug biotransformation an overview sciencedirect topics. Mar 03, 2014 biotransformation pathways drug metabolism reactions have been divided into two classes. They are generally associated with phase ii reactions, although some oxidation and reduction enzymes are contained in the cytosol. Biotransformation also plays an essential role in the toxicity of many chemicals due to the metabolic formation of toxic metabolites. Nov 02, 2014 additional examples of prodrugs and metric unit conversion discussion. These reactions expose or introduce a functional group oh, nh 2, sh, or cooh, and usually result in only a small increase in hydrophilicity. In phase i reactions, a small polar group containing both positive and negative charges is either exposed on the toxicant or added to the toxicant. Phase 1 reactions are also called functionalization or asynthetic reactions.
The process of drug biotransformation is classified into phase i and phase ii reactions, which occur sequentially and in most situations serve to terminate biological activity and enhance elimination. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the. The role of biotransformation and bioactivation in. 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. Activate naturalendogenous compounds for normal function. The role of biotransformation in the estrogenicity of xenobiotics. Phase i biotransformation is essential for the detoxification of xenobiotics, but in some cases, metabolic activation occurs, rendering the intermediate compounds even more toxic than the parent compounds guengerich, 1992. This chapter focuses on phase ii biotransformation reactions also. Once drugs have undergone phase i metabolism, they become more polar and are easier to eliminate. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to increase reactivity. The metabolites of phase i metabolic reactions can either be directly excreted in the urine or undergo further metabolic reactions. Metabolites formed in phase 2 are unlikely to be pharmacologically active.
Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Explain the role of biotransformation in toxicokinetics. The most important enzyme system involved in phase i reactions are the cytochromes p450, also called the cytochrome p450 system or the mixed function oxidase mfo system, but now mostly called cyp450 or cyps by. The chemical reactions responsible for changing a lipophilic toxicant into a chemical form are known as phase i and phase ii biotransformations. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. The processes of biotransformation are enabled by the continuous array of chemical reactions that occur in the body.
Reactions that convert the parent drug to a more polar watersoluble or more reactive product by unmasking or inserting a polar functional group such as oh, sh, or nh 2 phase ii reactions reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate. Phase ii reactions, but it is possible that a drug undergoes either only phase. Phase ii reactions involve the conjugation of chemicals with an endogenous moiety, such as glucuronic acid or sulfate williams 1959. Chapters 2 and 3 deal with the chemistry of drug biotransformation, describing both phase i asynthetic and phase ii synthetic biotransformations and the enzymes that mediate them. Biotransformation an overview sciencedirect topics. Compare and contrast phase i and phase ii biotransformation reactions. Catabolic reactions include oxidation, reduction, and hydrolysis. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for. Introduction to phase i and ii metabolisms phase i. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Phase i biotransformation reactions are simple reactions compared to phase ii reactions. These reactions may occur simultaneously or sequentially.
Enzymatic reactions that result in the conjugation of large watersoluble, charged polarbiomolecules to. Phase i reactions represent the introduction of functional groups, whereas phase ii reactions are conjugations of such functional groups with endogenous, polar products. 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. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions.
Biotransformation reactions produce more polar, hydrophilic, biologically inactive molecules that are more readily excreted. A common example is the processing of glutathione conjugates to acetylcysteine mercapturic acid conjugates. Sn2 reaction with udpgamost important phase ii reaction, major pathway in many species except cats. Phase i and phase ii biotransformation reactions deranged. In the majority of cases, such processes are triggered by enzymes, which act as catalysts for biochemical.
Biotransformation reactions can also result in the formation of chemically stable metabolites with pharmacological activity on or off target 36. The physiology and biochemistry of biotransformation. The metabolic biotransformation reactions of xenobiotics encompasses changes in these chemicals produced by biological environments. Metabolic biotransformation of xenobiotics mammalian. The purpose of phase ii biotransformation is to perform conjugating reactions. On top of that, biotransformation can occur when drugs undergo further metabolic steps following conjugation, including things like covalent binding to dna and proteins.
Types biotransformation reactions 2 types phase i non synthetic functionalization a functional group is generated metabolite active or inactive phase ii synthetic conjugation an endogenous radical is conjugated metabolite is usually inactive 12. The enzymes of phase i metabolism, most notably the cytochrome. An important point to note is that some drugs dont undergo phase i metabolic reaction but instead are directly deactivated by phase ii reactions. Both cyps and fmos are nadphdependent and require oxygen for catalytic reactions. Polar functional groups are either introduced into the molecule or modified by oxidation, reduction or hydrolysis. In fact, biotransformation can have four possible outcomes. Drug metabolizing enzymes and biotransformation reactions. On the other hand, these conjugations also play an essential role in the toxicity. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids such as glycine. This is called conjugation and the product is called a conjugate. Phase i reactions introduce polar groups into the chemical, including carboxyl, epoxide, hydroxyl, sulfhydryl, amine, hydroxylamine, and imine. Phase ii biotransformation reactions include glucuronidation, sulfonation, methylation, acetylation, amino acids such as glycine, glutamic acid, and taurine.
The role of biotransformation and bioactivation in toxicity. In general, these conjugates are more soluble in water and more readily excretable. This chapter addresses the phase ii biotransformation reactions that a drug or its metabolite typically undergo. The biotransformed metabolite is more toxic than the original compound. Recall that phase i reactions involve functionalization of drugs through oxidation, reduction, and hydrolysis reactions.
Phase i reactions involve hydrolysis, reduction, and oxidation. Sequential metabolism of 2,3,7trichlorodibenzopdioxin 2,3,7tricdd by cytochrome p450 and udpglucuronosyltransferase in human liver microsomes. After phase ii reactions, the xenobiotic conjugates may be further metabolized. Class is principles of drug action this problem has been solved. Phase i and phase ii reactions of drug authorstream presentation. Learning objectives, 2 identify tissues and factors involved in biotransformation. Apr 27, 2020 biotransformation occurs most often inside the liver, but it also occurs in the kidneys, lungs, skin, and intestines. The classification into phases has been questioned, as many compounds do not neatly follow such a linear chain of phase i and phase ii reactions and phase iii transport, but may only undergo one. Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities.
Principles of environmental toxicology 3 learning objectives, 2 identify tissues and factors. Enhanced phase ii detoxification contributes to beneficial. Introduction to phase i and ii metabolisms phase i metabolism. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2. Polar functional groups are either introduced into the molecule or. The mammalian drug biotransformation systems are thought to have first evolved from the need to detoxify and eliminate plant and bacterial bioproducts and toxins, which later extended to drugs and other environmental xenobiotics. Phase i reactions are functionalization reactions that introduce polar chemical moieties either by. This occurs by introduction of a polar group, such as hydroxyl oh, amine nh 2, and sulfhydryl sh groups for example, phenylbutazone is a benzene compound. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. An oh group is added to one of the benzene rings, yielding a parahydroxylated.
The pathways of biotransformation are divided into phase i, phase ii, and phase iii. This chapter focuses on phase ii biotransformation reactions also called. Pharmacologically active metabolites are generated through mainly primary andor secondary, and tertiary metabolism by phase i and phase ii. Phase ii enzymes play also an important role in the biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologically active substances.
Phase i reactions include oxidation, reduction, hydrolysis, or other reactions that modify chemicals in such a way that phase ii reactions may occur. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. Noriyuki k, toshiyuki s, raku s, shinichi i, takashi i, maya k, toshio o, miho o, kuniyo i. The final compounds have a larger molecular weight. Biotransformation is a process in which microorganisms convert organic compounds in to its structurally related products i. The final product is usually water soluble and, therefore, easier to excrete from the body.
The products are supposed to be significantly more hydrophilic than the original substrate. In general, biotransformation reactions are divided into two broad. The overall effect of these biotransformations is to increase. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. Reduced metabolising capacity of phase ii enzymes can lead to toxic effects of clinically used drugs. Drug biotransformation mechanisms are described as either phase i or phase ii reaction types. The biotransformation of benzene requires both phase i and phase ii reactions. Describe how biotransformation facilitates elimination of toxicants. Phase i and phase ii reactions of drug authorstream. The role of biotransformation in drug discovery and development.
This is followed by phase i hydrolysis to isonicotinic acid. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Reduction nadphcytochrome p450 reductase cytochrome p450 reductase also known as nadph. It is well believed that many such foods can prevent cancers hence the term chemoprevention by inducing phase ii detoxification systems 24 26. Phenol has a structure including a functional hydroxyl group that is then conjugated by a phase ii reaction sulfation to phenyl sulfate.
Biochemistry, biotransformation statpearls ncbi bookshelf. Phase ii biotransformation consists of conjugation of reactive groups, present either in the. Biotransformation drug metabolism linkedin slideshare. Compare and contrast phase i and phase ii biotrans. These reactions involve covalent attachment of small hydrophilic endogenous molecule such as glucuronic acid, sulfate, or glycine to form watersoluble compounds, that are more hydrophilic. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to slightly increase hydrophilicity. Sometimes metabolites retain biological activity and may be toxic. Examples of each type of conjugation have been illustrated below. The beneficial effects of phase ii reactions have been particularly studied in relation to the mechanism of healthy dietary ingredients. Although dr also substantially reduces the incidence. As illustrated in figure 5, benzene is biotransformed initially to phenol by a phase i reaction oxidation. Biotransformation reactions and their enzymes sciencedirect. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups.
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