A review of Bioactivation and Tissue Toxicity

A review of Bioactivation and Tissue ToxicityKong 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 are foreign chemicals in the body 1. The human body has adapted processes collectively termed as biotrans geological take shapeation to excrete these xenobiotics 1,2. Biotransformation generally occurs sequentially in ii anatomys 1,2. Phase I reactions add juvenile functional groups to the elicit compound while phase II reactions conjugate these new functional groups with polar groups 1,2. The end-result of biotransformation is rock-bottom lipid solubility, thus increasing renal excretion 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. Occasionally, bioactivation occurs, in which the inert parent co mpound is modified into toxic metabolites 1,3,4. The toxic metabolites are either electrophiles or shrive radicals, which interact with body wanders, subsequently causing toxicity 3,5.ElectrophilesElectrophiles are species lacking(p) in electron pair generated through Phase 1 metabolism by CYP450 5. They are short-lived (with the possible exception of some acyl glucuronides) and not usually detectable in circulation 5. Electrophiles can be generated from carbon, nitrogen or sulphur containing compounds 4. The most frequently metabolised structural alerts are aromatic systems with electron-donating substituents and some membered heterocyclic 6.Electrophiles character toxicity through the formation of irreversible covalent bond to nucleophilic tissue components which includes macromolecules (proteins, nucleic acids and lipids) or low molecular weight mobile phoneular constituents 4. covalent binding generates potent and long lasting toxic effects because the covalently modifie d enzyme/receptor is permanently inactivated 4. The covalent binding to deoxyribonucleic acid leads to mutation, tissue necrosis, carcinogenicity and tumour formation 4. Mutations arise when the electrophiles escape the repair mechanisms of the cell, may be fixed 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 radicalsFree radicals (species containing an odd number of electrons) may be cations, anions or neutral radicals 8. Free radicals are generally formed via NADPH CYP450 reductase or other flavin containing reductases 8. They will toxicity by per oxidization of cellular components. An important class of renounce radicals is organic free radicals such as hydrogen peroxide and superoxide anion 8. The potential toxicity of free radicals is far greater than electrophiles 8.Free radicals are able to construct chemical modifications and damage to proteins, lipids, carbohydrates and nucleotides 9. If the thermolabile free radical is formed close to DNA past it may produce a change in the building resulting in a mutation or cytotoxicity 9. Protein and non-protein thiol groups are readily oxidized by many free radicals and may lead to profound changes in enzyme activity 9. Another major pathway of metabolic disturbances is depending on covalent binding with cell components such as protein, lipid and nucleic acid to from a stable covalently bound adduct that may grossly distort structure and function 9. Reactive free radical may also damage cells through membrane damage 9. Examples of free radicals include hydrogen peroxide, hydroxyl radical and peroxynitrite 10.Examples of drugs undergoing bioactivation and causing subsequent tissue toxicityTable 1 Several drugs, with their corresponding toxic metabolic pathways and the subsequent adverse effects. medicineMetabolic pathwayAdverse effect schloramphenicolChloramphenicol is first oxidised by CYP monooxygenase into its dichloromethyl moiety 11. Hydrochloric acid is then eliminated to produce a excited metabolite that interacts with the -amino acid of a lysine residue in CYP monooxygenase 11. The enzymatic reaction is eventually retards over time, leading to adverse effects 11.Apalstic anemia 12Bone marrow toxicity 12AcetaminophenThe reactive metabolite is called N-acetyl-p-benzoquinone imine (NAPQI) 11.Metabolic pathway 1 Acetaminophen undergoes N-oxidation to become 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 oxidised by CYP2C9 to either thiophene sulfoxide or thiophene epoxide 11. These electrophilic re active 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 complex 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 newly formed neoantigen evokes an immune repartee towards the liver 11.Severe hepatitis 11Valproic acidValproic acid is metabolised by CYP2C9 into 2-propyl-4-pentenoic aci d, also termed as 4VPA 11. This metabolite can then undergo two pathways 11.Metabolic pathway 1 CYP enzymes metabolise 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 spontaneously 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 path way 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.Hepatic failureDeath (due to hepatic failure) 11.Part 2 Applications of Bioactivation and Tissue Toxicity in Abacavir and LidocaineAbacavirAbacavir (first principle) is an anti-HIV drug classified as a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) 13. ABC possesses a significant role in the turnment 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-carboxylate involves a two-step oxidation via an aldehyde intermediate (unconjugated ABC-aldehyd e) which rapidly tautomerizes to the more 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 deep down the first 6 weeks of treatment 13. ABC also possesses the potential to induce cardiotoxicity, which raised further concerns about the prolonged administration of this drug 13.LidocaineLidocaine has been extensively apply 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 uneasy and cardiac toxicity 14,15. Early signs of CNS 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 free radicals) may be produced in processes called bioactivation, which interact with body tissues and cause tissue toxicity. The bi oactivation 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 risk and drug design. Annual review of pharmacology and toxicology. 2011 51 145-67.4 Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics A Treatise. 2nd 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. 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