A review of Bioactivation and Tissue Toxicity

✅ Paper Type: Free Essay	✅ Subject: Chemistry
✅ Wordcount: 2261 words	✅ Published: 28th Nov 2017

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Kong 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)

Introduction

Xenobiotics are foreign chemicals in the body [1]. The human body has adapted processes collectively termed as biotransformation to excrete these xenobiotics [1,2]. Biotransformation generally occurs sequentially in two phases [1,2]. Phase I reactions add new functional groups to the parent 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 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 compound is modified into toxic metabolites [1,3,4]. The toxic metabolites are either electrophiles or free radicals, which interact with body tissues, subsequently causing toxicity [3,5].

Electrophiles

Electrophiles are species deficient 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 five-membered heterocyclic [6].

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Electrophiles cause toxicity through the formation of irreversible covalent bond to nucleophilic tissue components which includes macromolecules (proteins, nucleic acids and lipids) or low molecular weight cellular constituents [4]. Covalent binding generates potent and long lasting toxic effects because the covalently modified enzyme/receptor is permanently inactivated [4]. The covalent binding to DNA 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 radicals

Free 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 provide toxicity by peroxidation of cellular components. An important class of free 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 produce chemical modifications and damage to proteins, lipids, carbohydrates and nucleotides [9]. If the reactive free radical is formed close to DNA then 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 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 toxicity

Table 1: Several drugs, with their corresponding toxic metabolic pathways and the subsequent adverse effects.

Drug	Metabolic pathway	Adverse effects
Chloramphenicol	Chloramphenicol is first oxidised by CYP monooxygenase into its dichloromethyl moiety [11]. Hydrochloric acid is then eliminated to produce a reactive metabolite that interacts with the Æ-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 [12] Bone marrow toxicity [12]
Acetaminophen	The 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 acid	Tienilic acid is oxidised 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 [11]
Halothane	Matabolic 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 σ-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 Æ-NH₂-lysyl residue [11]. This newly formed neoantigen evokes an immune response towards the liver [11].	Severe hepatitis [11]
Valproic acid	Valproic acid is metabolised by CYP2C9 into 2-propyl-4-pentenoic acid, also termed as Δ⁴VPA [11]. This metabolite can then undergo two pathways [11]. Metabolic pathway 1: CYP enzymes metabolize Δ⁴VPA 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 Δ⁴VPA metabolite undergoes β-oxidation to generate the Coenzyme A ester of 3-oxo-2-propyl-4-pentenoic acid [11]. This new metabolite alkylates the terminal enzyme of β-oxidation (3-ketoacyl-CoA thiolase) by a nucleophilic attack at the olefinic terminus [11].	Hepatotoxicity [11]
Troglitazone	Metabolic 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 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].	Hepatic failure Death (due to hepatic failure) [11].

Part 2: Applications of Bioactivation and Tissue Toxicity in Abacavir and Lidocaine

Abacavir

Abacavir (ABC) is an anti-HIV drug classified as a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) [13]. ABC possesses a significant role in the treatment 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-aldehyde) 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 within 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].

Lidocaine

Lidocaine has been extensively used 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 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].

Conclusion

To 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 bioactivation and subsequent adverse effects of abacavir and lidocaine has been discussed in detail.

References

[1] Rang H, Dale M, Ritter J. Rang & Dale’s pharmacology. 7^th 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. 2^nd Edition. Vallabh Publications Prakashan; 2012.

[5] Boyer T, Manns M, Sanyal A, Zakim D. Zakim and Boyer’s 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 Chemicals,Current Topics in Medicinal Chemistry. 2004; 4:1767-88.

[8] Leon Shargel , Andrew Yu, Suzanna Wu-Pong. Applied Biopharmaceutics & Pharmacokinetics. 6^th ed. USA :McGraw Hill ; 2012.

[9] Trevor F. Slater. Free-radical mechanisms in tissue injury. Biochem J. 1984 Aug 15;222(1):1-15.

[10] V. Lobo, A. Patil, A. Phatak, N. Chandra. Free radicals and functional foods : impact on human health. Pharmacogn Rev. 2010 Dec; 4(8): 118-26

[11] Wermuth CG, editor. The Practice of Medicinal Chemistry. 3^rd edition. UK and USA: 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. 1974;50:1217-30.

[15] Johansen Ø. Comparison of Articaine and Lidocaine used as Dental Local Anesthetics. Faculty of Dentistry, University of Oslo; 2004. 25 p.