Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymaticmetabolism in the organisms, as well as by abioticchemical reactions. While the parent drug are usually less active, both the parent drug and its metabolite can be chemically active and cause toxicity, leading to mutagenesis, teratogenesis, and carcinogenesis.[1][2] Different classes of enzymes, such as P450-monooxygenases, epoxide hydrolase, or acetyltransferases can catalyze the process in the cell, mostly in the liver.[2]
Parent non-toxic chemicals are generally referred to as protoxins. While toxication is generally undesirable, in certain cases it is required for the in vivo conversion of a prodrug to a metabolite with desired pharmacological or toxicological activity. Codeine is an example of a prodrug, metabolized in the body to the active compounds morphine and codeine-6-glucuronide.
Enzyme CYP3A4, in CYP3A subfamily, contributes to hepatotoxicity during metabolism.
Phase I of drug metabolism are bioactivation pathways, which are catalyzed by CYP450 enzymes, produce toxic metabolites and thus have the potential to damage cells. The unusual level of activity CYP450 enzymes might lead to the changes in drug metabolism and convert drugs into their more toxic forms. Among Phase I CYP450 enzymes, the subfamilies CYP2D6 and CYP3A are responsible for hepatotoxicity during drug metabolism with a number of different drugs, including flucloxacilin, trioleandomycin, and troglitazone.[3] Hepatotoxicity indicates the drug's toxicity to liver.
Paracetamol (acetaminophen, APAP) is converted into the hepatotoxic metabolite NAPQI via the cytochrome P450 oxidase system, mainly by the subfamily CYP2E1. Hepatic reduced glutathione (GSH) will detoxify this formed NAPQI quickly by if APAP is taken at a proper level. In the case of overdoses, the storage of GSH will not be enough for NAPQI detoxication, thereby resulting in acute liver injury.[4]
Other oxidoreductasesedit
Oxidoreductases are enzymes that catalyze the reactions that involve the transfer of electrons. Methanol in itself is toxic due to its central nervous system depression properties, but it can be converted to formaldehyde by alcohol dehydrogenase and then converted to formic acid by aldehyde dehydrogenase, which are significantly more toxic. Formic acid and formaldehyde can cause severe acidosis, damage to the optic nerve, and other life-threatening complications.[5]
Ethylene glycol (common antifreeze) can be converted into toxic glycolic acid, glyoxylic acid and oxalic acid by aldehyde dehydrogenase, lactate dehydrogenase (LDH) and glycolate oxidase in mammalian organisms.[5][6] The accumulation of the end product of the ethylene glycol mechanism, calcium oxalate, may cause malfunction in the kidney and lead to more severe consequences.[5]
Other examplesedit
Other examples of toxication by enzymatic metabolism include:
Conversion of secondary amines in the stomach into carcinogenic nitrosamines via NO pathway.[7]
Nicotine into the nitrosated carcinogenic NNK (4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone) in the lung.[8]
Benzo[a]pyrene into the carcinogenic benzo[a]pyrene diol epoxide (BP-7,8-dihydrodiol-9,10-epoxide)
Increases in toxicity can also be caused by abioticchemical reactions. Non-living elements affect the abiotic chemical reactions. Anthropogenic trace compounds (ATCs) have potential toxicity to the organisms in aquatic system.[9]
Arsenic contamination in drinking water can be chemically toxic. The uptake and metabolism of arsenic may result the damage to body. When organic arsenic is converted into more toxic inorganic arsenic, it causes carcinogenesis, cytotoxicity (toxic to cells) and genotoxicity (causing mutations in genes).[10]
^Pirmohamed, Dr Munir; Kitteringham, Neil R.; Park, B. Kevin (2012-10-26). "The Role of Active Metabolites in Drug Toxicity". Drug Safety. 11 (2): 114–144. doi:10.2165/00002018-199411020-00006. ISSN 0114-5916. PMID 7945999. S2CID 24956095.
^ abMeyer, Urs A. (1996-10-01). "Overview of enzymes of drug metabolism". Journal of Pharmacokinetics and Biopharmaceutics. 24 (5): 449–459. doi:10.1007/BF02353473. ISSN 0090-466X. PMID 9131484. S2CID 22586901.
^Michaut, Anaïs; Moreau, Caroline; Robin, Marie-Anne; Fromenty, Bernard (2014-08-01). "Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease". Liver International. 34 (7): e171–e179. doi:10.1111/liv.12514. ISSN 1478-3231. PMID 24575957.
^ abcKruse, James A. (2012). "Methanol and Ethylene Glycol Intoxication". Critical Care Clinics. 28 (4): 661–711. doi:10.1016/j.ccc.2012.07.002. PMID 22998995.
^Wayne Wingfield; Marc Raffe (29 September 2002). The Veterinary ICU Book. Teton NewMedia. pp. 1042–. ISBN978-1-893441-13-2.
^d’Ischia, Marco; Napolitano, Alessandra; Manini, Paola; Panzella, Lucia (2011-09-30). "Secondary Targets of Nitrite-Derived Reactive Nitrogen Species: Nitrosation/Nitration Pathways, Antioxidant Defense Mechanisms and Toxicological Implications". Chemical Research in Toxicology. 24 (12): 2071–2092. doi:10.1021/tx2003118. PMID 21923154.
^Brunnemann, Klaus D.; Prokopczyk, Bogdan; Djordjevic, Mirjana V.; Hoffmann, Dietrich (1996-01-01). "Formation and Analysis of Tobacco-SpecificN-Nitrosamines". Critical Reviews in Toxicology. 26 (2): 121–137. doi:10.3109/10408449609017926. ISSN 1040-8444. PMID 8688156.
^Gerbersdorf, Sabine U.; Cimatoribus, Carla; Class, Holger; Engesser, Karl-H.; Helbich, Steffen; Hollert, Henner; Lange, Claudia; Kranert, Martin; Metzger, Jörg (2015-06-01). "Anthropogenic Trace Compounds (ATCs) in aquatic habitats — Research needs on sources, fate, detection and toxicity to ensure timely elimination strategies and risk management". Environment International. 79: 85–105. doi:10.1016/j.envint.2015.03.011. PMID 25801101.
^Shankar, Shiv; Shanker, Uma; Shikha (2014-01-01). "Arsenic contamination of groundwater: a review of sources, prevalence, health risks, and strategies for mitigation". TheScientificWorldJournal. 2014: 304524. doi:10.1155/2014/304524. ISSN 1537-744X. PMC4211162. PMID 25374935.
March 18, 2024
toxication, toxification, toxicity, exaltation, conversion, chemical, compound, into, more, toxic, form, living, organisms, substrates, such, soil, water, conversion, caused, enzymatic, metabolism, organisms, well, abiotic, chemical, reactions, while, parent, . Toxication toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water The conversion can be caused by enzymatic metabolism in the organisms as well as by abiotic chemical reactions While the parent drug are usually less active both the parent drug and its metabolite can be chemically active and cause toxicity leading to mutagenesis teratogenesis and carcinogenesis 1 2 Different classes of enzymes such as P450 monooxygenases epoxide hydrolase or acetyltransferases can catalyze the process in the cell mostly in the liver 2 Parent non toxic chemicals are generally referred to as protoxins While toxication is generally undesirable in certain cases it is required for the in vivo conversion of a prodrug to a metabolite with desired pharmacological or toxicological activity Codeine is an example of a prodrug metabolized in the body to the active compounds morphine and codeine 6 glucuronide Contents 1 Toxication by enzymatic metabolism 1 1 CYP450 enzymes 1 2 Other oxidoreductases 1 3 Other examples 2 Toxication by abiotic chemical reactions 3 See also 4 ReferencesToxication by enzymatic metabolism editCYP450 enzymes edit nbsp Enzyme CYP3A4 in CYP3A subfamily contributes to hepatotoxicity during metabolism Phase I of drug metabolism are bioactivation pathways which are catalyzed by CYP450 enzymes produce toxic metabolites and thus have the potential to damage cells The unusual level of activity CYP450 enzymes might lead to the changes in drug metabolism and convert drugs into their more toxic forms Among Phase I CYP450 enzymes the subfamilies CYP2D6 and CYP3A are responsible for hepatotoxicity during drug metabolism with a number of different drugs including flucloxacilin trioleandomycin and troglitazone 3 Hepatotoxicity indicates the drug s toxicity to liver Paracetamol acetaminophen APAP is converted into the hepatotoxic metabolite NAPQI via the cytochrome P450 oxidase system mainly by the subfamily CYP2E1 Hepatic reduced glutathione GSH will detoxify this formed NAPQI quickly by if APAP is taken at a proper level In the case of overdoses the storage of GSH will not be enough for NAPQI detoxication thereby resulting in acute liver injury 4 Other oxidoreductases edit Oxidoreductases are enzymes that catalyze the reactions that involve the transfer of electrons Methanol in itself is toxic due to its central nervous system depression properties but it can be converted to formaldehyde by alcohol dehydrogenase and then converted to formic acid by aldehyde dehydrogenase which are significantly more toxic Formic acid and formaldehyde can cause severe acidosis damage to the optic nerve and other life threatening complications 5 nbsp Ethylene glycol common antifreeze can be converted into toxic glycolic acid glyoxylic acid and oxalic acid by aldehyde dehydrogenase lactate dehydrogenase LDH and glycolate oxidase in mammalian organisms 5 6 The accumulation of the end product of the ethylene glycol mechanism calcium oxalate may cause malfunction in the kidney and lead to more severe consequences 5 nbsp Other examples edit Other examples of toxication by enzymatic metabolism include Conversion of secondary amines in the stomach into carcinogenic nitrosamines via NO pathway 7 Nicotine into the nitrosated carcinogenic NNK 4 methylnitrosamino 1 3 pyridyl 1 butanone in the lung 8 Benzo a pyrene into the carcinogenic benzo a pyrene diol epoxide BP 7 8 dihydrodiol 9 10 epoxide Hypoglycin A into the highly toxic MCPA CoAToxication by abiotic chemical reactions editIncreases in toxicity can also be caused by abiotic chemical reactions Non living elements affect the abiotic chemical reactions Anthropogenic trace compounds ATCs have potential toxicity to the organisms in aquatic system 9 Arsenic contamination in drinking water can be chemically toxic The uptake and metabolism of arsenic may result the damage to body When organic arsenic is converted into more toxic inorganic arsenic it causes carcinogenesis cytotoxicity toxic to cells and genotoxicity causing mutations in genes 10 See also editChelation therapy DetoxificationReferences edit Pirmohamed Dr Munir Kitteringham Neil R Park B Kevin 2012 10 26 The Role of Active Metabolites in Drug Toxicity Drug Safety 11 2 114 144 doi 10 2165 00002018 199411020 00006 ISSN 0114 5916 PMID 7945999 S2CID 24956095 a b Meyer Urs A 1996 10 01 Overview of enzymes of drug metabolism Journal of Pharmacokinetics and Biopharmaceutics 24 5 449 459 doi 10 1007 BF02353473 ISSN 0090 466X PMID 9131484 S2CID 22586901 Andrade Raul J Robles Mercedes Ulzurrun Eugenia Lucena M Isabel 2009 Drug induced liver injury insights from genetic studies Pharmacogenomics 10 9 1467 1487 doi 10 2217 pgs 09 111 PMID 19761370 Michaut Anais Moreau Caroline Robin Marie Anne Fromenty Bernard 2014 08 01 Acetaminophen induced liver injury in obesity and nonalcoholic fatty liver disease Liver International 34 7 e171 e179 doi 10 1111 liv 12514 ISSN 1478 3231 PMID 24575957 a b c Kruse James A 2012 Methanol and Ethylene Glycol Intoxication Critical Care Clinics 28 4 661 711 doi 10 1016 j ccc 2012 07 002 PMID 22998995 Wayne Wingfield Marc Raffe 29 September 2002 The Veterinary ICU Book Teton NewMedia pp 1042 ISBN 978 1 893441 13 2 d Ischia Marco Napolitano Alessandra Manini Paola Panzella Lucia 2011 09 30 Secondary Targets of Nitrite Derived Reactive Nitrogen Species Nitrosation Nitration Pathways Antioxidant Defense Mechanisms and Toxicological Implications Chemical Research in Toxicology 24 12 2071 2092 doi 10 1021 tx2003118 PMID 21923154 Brunnemann Klaus D Prokopczyk Bogdan Djordjevic Mirjana V Hoffmann Dietrich 1996 01 01 Formation and Analysis of Tobacco SpecificN Nitrosamines Critical Reviews in Toxicology 26 2 121 137 doi 10 3109 10408449609017926 ISSN 1040 8444 PMID 8688156 Gerbersdorf Sabine U Cimatoribus Carla Class Holger Engesser Karl H Helbich Steffen Hollert Henner Lange Claudia Kranert Martin Metzger Jorg 2015 06 01 Anthropogenic Trace Compounds ATCs in aquatic habitats Research needs on sources fate detection and toxicity to ensure timely elimination strategies and risk management Environment International 79 85 105 doi 10 1016 j envint 2015 03 011 PMID 25801101 Shankar Shiv Shanker Uma Shikha 2014 01 01 Arsenic contamination of groundwater a review of sources prevalence health risks and strategies for mitigation TheScientificWorldJournal 2014 304524 doi 10 1155 2014 304524 ISSN 1537 744X PMC 4211162 PMID 25374935 Retrieved from https en wikipedia org w index php title Toxication amp oldid 1188502886, wikipedia, wiki, book, books, library,
