A review of Bioactivation and Tissue Toxicity

A review of Bioactivation and create from raw stuff perniciousnessKong Wei En (BP0711031415)Raymond Koh Chee How (BP0711031287)Jennie Lee Sheah Lin (BP0711031372)Prashanthini A/P Janardanan (BP0711031156)Hong Wei Siong (BP0711031194)Shalini A/P Shanmugavelu (BP0711031145)IntroductionXenobiotics atomic number 18 foreign chemical substances in the organic structure 1. The human body has adapted processes collectively termed as biotrans put to workation to excrete these xenobiotics 1,2. Biotrans progress toation generally occurs sequentially in two phases 1,2. Phase I reactions add new in operation(p) meetings to the provoke compound while phase II reactions conjugate these new functional groups with polar groups 1,2. The end-result of biotransformation is decreased lipid solubility, thus increasing renal elimination 1,2. The liver is the chief site for biotransformation, 1,2. Enzymes such as cytochrome P450 and peroxidase enzymes are responsible for biotransformation 3,4. Occ asionally, bioactivation occurs, in which the inert parent compound is modify into ototoxic metabolites 1,3,4. The toxic metabolites are either electrophiles or free stalks, which interact with body tissues, after make toxicity 3,5.ElectrophilesElectrophiles are species deficient in electron gibe generated through Phase 1 metabolism by CYP450 5. They are transient (with the possible exception of some acyl glucuronides) and not usually perceptible in circulation 5. Electrophiles can be generated from carbon, nitrogen or sulphur containing compounds 4. The well-nigh frequently metabolised structural alerts are smelling(p) remainss with electron-donating substituents and some five-membered cyclic 6.Electrophiles cause toxicity through the formation of irreversible covalent dumbfound to nucleophilic tissue components which includes macromolecules (proteins, nucleic blisterings and lipids) or low molecular weight cubicleular constituents 4. covalent binding generates poten t and long lasting toxic effects because the covalently special enzyme/receptor is permanently inactivated 4. The covalent binding to DNA leads to mutation, tissue necrosis, carcinogenicity and neoplasm formation 4. Mutations arise when the electrophiles escape the repair mechanisms of the cellphone, whitethorn be stiff and passed to the progeny 4. If the electrophiles bind to protein, they will disturb the physiological homeostasis, leading to cell death 7. Examples of electrophiles include epoxide, hydroxylamines and aldehydes 4,5.Free ascendentsFree radicals (species containing an odd number of electrons) may be cations, anions or neutral radicals 8. Free radicals are generally make via NADPH CYP450 reductase or other flavin containing reductases 8. They provide toxicity by per oxidisation of cellular components. An all important(p) class of free radicals is organic free radicals such as enthalpy peroxide and superoxide anion 8. The potential toxicity of free radicals is far great than electrophiles 8.Free radicals are able to produce chemical modifications and damage to proteins, lipids, carbohydrates and nucleotides 9. If the labile free radical is formed close to DNA therefore it may produce a change in the structure resulting in a mutation or cytotoxicity 9. Protein and non-protein thiol groups are readily oxidized by umpteen free radicals and may lead to profound changes in enzyme activity 9. other major street of metabolic disturbances is depending on covalent binding with cell components such as protein, lipid and nucleic venomous to from a stable covalently sharpness adduct that may grossly distort structure and function 9. activated free radical may also damage cells through tissue layer damage 9. Examples of free radicals include hydrogen peroxide, hydroxyl radical and peroxynitrite 10.Examples of drugs undergoing bioactivation and causing incidental tissue toxicityTable 1 Several drugs, with their interchangeable toxic metaboli c highways and the subsequent ominous effects.DrugMetabolic highroadAdverse effectsChloramphenicolChloramphenicol is set-back oxidised by CYP monooxygenase into its dichloromethyl moiety 11. Hydrochloric acid is then eliminated to produce a labile metabolite that interacts with the -amino acid of a lysine residue in CYP monooxygenase 11. The enzymatic reaction is eventually retards everywhere time, leading to adverse effects 11.Apalstic anemia 12Bone marrow toxicity 12AcetaminophenThe reactive metabolite is called N-acetyl-p-benzoquinone imine (NAPQI) 11.Metabolic roadway 1 Acetaminophen undergoes N-oxidation to plump N-hydroxyacetaminophen, which then undergoes dehydration to form NAPQI 11. This pathway is probably uncommon as N-hydroxyacetaminophen is not a chief intermediate in the oxidation of acetaminophen 11.Metabolic pathway 2 NAPQI undergoes a Michael-type addition with either glutathione or protein thiol groups 11.Hepatotoxicity 11,12.Tienilic acidTienilic acid is o xidised by CYP2C9 to either thiophene sulfoxide or thiophene epoxide 11. These electrophilic reactive intermediates alkylate CYP2C9, permanently binding themselves to the enzyme 11. The enzyme is subsequently inactivated 11. The body then produces anti-LKM2 autoantibodies against the native CYP2C9 enzyme and the modified CYP2C9 enzyme 11.Immunoallergic hepatitis 11HalothaneMatabolic pathway 1 In hypoxic states, halothane undergoes reduction to produce the 1-chloro-2,2,2-trifluoroethyl free radical 11. This free radical performs a radical attack, leading to the necrosis of hepatocytes 11. The radical may also react with the Fe2+ in the CYP enzyme to form an iron -alkyl multiplex 11. This complex then causes the necrosis of the hepatocytes 11.Metabolic pathway 2 Halothane undergoes oxidation to produce trifluoroacetyl chloride 11. Liver proteins are then trifluoroacetylated on their -NH2-lysyl residue 11. This new formed neoantigen evokes an immune response towards the liver 11.Seve re hepatitis 11Valproic acidValproic acid is metabolised by CYP2C9 into 2-propyl-4-pentenoic acid, also termed as 4VPA 11. This metabolite can then undergo two pathways 11.Metabolic pathway 1 CYP enzymes metabolize 4VPA into a reactive metabolite, which then proceeds to alkylate the prosthetic heme of the CYP enzymes 11. Hence, the enzymes are inhibited 11.Metabolic pathway 2 The 4VPA metabolite undergoes -oxidation to generate the Coenzyme A ester of 3-oxo-2-propyl-4-pentenoic acid 11. This new metabolite alkylates the terminal enzyme of -oxidation (3-ketoacyl-CoA thiolase) by a nucleophilic attack at the olefinic terminus 11.Hepatotoxicity 11TroglitazoneMetabolic pathway 1 The thiazolidinedione ring undergoes oxidative cleavage to produce a reactive sulfoxide intermediate, which ad lib opens its ring 11.Metabolic pathway 2 The phenolic hydroxyl group of troglitazone undergoes a one-electron oxidation catalysed by CYP3A to produce an unstable hemiacetal, which spontaneously opens to form a quinine metabolite 11. The quinine metabolite then undergoes the metabolic pathway described earlier (metabolic pathway 1) 11.Metabolic pathway 3 The unstable hemiacetal produced in metabolic pathway 2 may undego hydrogen abstraction, resulting in the production of an o-quinone methide derivative 11. liverwort failureDeath (due to hepatic failure) 11.Part 2 Applications of Bioactivation and Tissue Toxicity in Abacavir and LidocaineAbacavirAbacavir ( rudiment) is an anti-HIV drug classified as a nucleoside/nucleotide move up transcriptase inhibitor (NRTI) 13. ABC possesses a significant region in the discussion of HIV patients 13. First, ABC is subjected to phase I oxidation to produce ABC-carboxylate, followed by phase II glucuronidation to generate the inactive glucuronide metabolite 13. Both the glucuronide and carboxylate metabolites are chiefly eliminated in the urine 13.ABC undergoes bioactivation to form reactive aldehyde metabolites 13. ABC metabolism to ABC-carb oxylate involves a two-step oxidation via an aldehyde intermediate (unconjugated ABC-aldehyde) which rapidly tautomerizes to the to a greater extent stable conjugated ABC-aldehyde 13. This reactive metabolite is capable of reacting with proteins to produce covalent adducts, which results in the occurrence of adverse effects 13.The most prevalent acute ABC-induced adverse effects are the potentially life-threatening hypersensitivity reactions (HSR) that occur within the first 6 weeks of airinessment 13. ABC also possesses the potential to induce cardiotoxicity, which raised(a) further concerns about the prolonged administration of this drug 13.LidocaineLidocaine has been extensively use in the treatment of ventricular arrhythmias 14. It is also usually administered intravenously to treat and prevent cardiac arrhythmias after acute myocardial infarction 14. Its chemical structure is an amide with an aromatic group 15. Lidocaine is chiefly metabolized by the microsomal enzyme system in the liver 15.The major biotransformation pathways are oxidation and hydroxylation 14. Lidocaine undergoes oxidative N-deethylation to form the toxic mono-ethylglycinexylidide, which is then hydrolysed to 2,6-xylidine 14,15. Finally, 2,6-xylidine is modified to 4-hydroxy-2,6-xylidine, which is excreted in urine 14. Lidocaine also undergoes hydroxylation of the aromatic nitrogen to form N-hydroxylidocaine and the toxic N-hydroxymonoethylglycinexylidide 14.The active and toxic metabolites known as mono-ethylglycinexylidide and N-hydroxymonoethylglycinexylidide primarily cause neural and cardiac toxicity 14,15. Early signs of systema nervosum centrale intoxication include shivering, muscular twitching and tremors of the facial muscles 15. As toxicity is low, it is safely and extensively used to treat arrhythmias 15.ConclusionTo eliminate xenobiotics from our body, processes collectively termed as biotransformation occurs in two phases. However, toxic metabolites (electrophiles or fre e radicals) may be produced in processes called bioactivation, which interact with body tissues and cause tissue toxicity. The bioactivation and subsequent adverse effects of abacavir and lidocaine has been discussed in detail.References1 Rang H, Dale M, Ritter J. Rang Dales pharmacology. 7th Edition. Edinburgh Churchill Livingstone 2011.2 Dekant W. The role of biotransformation and bioactivation in toxicity. Springer. 2009 57-86.3 Walsh J, Miwa G. Bioactivation of drugs try and drug design. Annual review of pharmacology and toxicology. 2011 51 145-67.4 Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics A Treatise. second Edition. Vallabh Publications Prakashan 2012.5 Boyer T, Manns M, Sanyal A, Zakim D. Zakim and Boyers hepatology. Philadelphia, PA Saunders/Elsevier 2012.6 Walsh J, Miwa G. Bioactivation of drugs risk and drug design. Annual review of pharmacology and toxicology. 2011 51 145-67.7 Ioannides C, Lewis DFV. Cytochromes P450 in the Bioactivation of Chemi cals,Current Topics in Medicinal Chemistry. 2004 41767-88.8 Leon Shargel , Andrew Yu, Suzanna Wu-Pong. Applied Biopharmaceutics Pharmacokinetics. 6th ed. the States McGraw Hill 2012.9 Trevor F. Slater. Free-radical mechanisms in tissue injury. Biochem J. 1984 Aug 15222(1)1-15.10 V. Lobo, A. Patil, A. Phatak, N. Chandra. Free radicals and functional foods reach on human health. Pharmacogn Rev. 2010 Dec 4(8) 118-2611 Wermuth CG, editor. The Practice of Medicinal Chemistry. 3rd edition. UK and ground forces Elsevier Ltd. 2008.12 Nassar AF, Hollenberg PF, Scatina J, editors. Drug Metabolism Handbook Concepts and Applications. New Jersey and Canada John Wiley Sons, Inc. 2009.13 Griloa NM, Charneirab C, Pereiraa SA, et al. Bioactivation to an aldehyde metabolite-Possible role in the onset of toxicity induced by the anti-HIV drug abacavir. Toxicology Letters. 2014 224 416-23.14 Collinsworth KA, Kalman SM, Harrison DC. The clinical Pharmacology of Lidocaine as an Antiarrhythmic Drug. Circulation. 1974501217-30.15 Johansen . Comparison of Articaine and Lidocaine used as Dental Local Anesthetics. Faculty of Dentistry, University of Oslo 2004. 25 p.