Skip to main content

Xenobiotic Bioactivation-Mediated Cellular Damages

  • Chapter
  • First Online:
Xenobiotic Metabolic Enzymes: Bioactivation and Antioxidant Defense
  • 372 Accesses

Abstract

Besides natural toxins, many toxicities are resulted from metabolic activation of foreign compounds that leads to the formation of reactive intermediate species and metabolites. Oxidative stresses generated from xenobiotic metabolism are potentially capable of interacting with endogenous targets, triggering perturbation in cellular functions and resulting in cellular damages. Covalent binding of reactive intermediates to cellular components results in forming protein and DNA adducts and causing lipid peroxidation. The extent of foreign compound toxicities depends on its nature, metabolic enzymes, and environmental factors and includes natural toxicity, bioactivation-mediated toxicity, and induced toxicity. Xenobiotic bioactivation-mediated cellular damagesĀ also include mitochondrial function intervention, interference with ion transporters and enzymatic functions, and immune suppression and stimulation effects. Due to the generation of toxic reactive intermediate in the course of drug metabolism, adverse drug reactions are an important research area.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Bibliography

  • Arispe N, Diaz JC, Simakova O et al (2008) Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels. Proc Natl Acad Sci U S A 105:2610ā€“2615

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Blaikie FH, Brown SE, Samuelsson LM et al (2006) Targeting dinitrophenol to mitochondria: limitations to the development of a self-limiting mitochondrial protonophore. Biosci Rep 26:231ā€“243

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Brzezinski MR, Boutelet-Bochan H, Person RE et al (1999) Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J Pharmacol Exp Ther 289:1648ā€“1653

    CASĀ  PubMedĀ  Google ScholarĀ 

  • Chen CH (2012) Activation and detoxification enzymes: functions and implications. Springer Sciences, New York

    BookĀ  Google ScholarĀ 

  • Choi DW, Leininger-Muller B, Wellman M et al (2004) Cytochrome p-450-mediated differential oxidative modification of proteins: albumin, apolipoprotein E, and CYP2E1 as targets. J Toxicol Environ Health A 67:2061ā€“2071

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Chou AP, Li S, Fitzmaurice AG et al (2010) Mechanisms of rotenone-induced proteasome inhibition. Neurotoxicology 31:367ā€“372

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Damsten MC, de Vlieger JS, Niessen WM, Irth H, Vermeulen NP, Commandeur JN (2008) Trimethoprim: novel reactive intermediates and bioactivation pathways by cytochrome p450s. Chem Res Toxicol 21(11):2181ā€“2187

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Dolan LC, Matulka RA, Burdock GA (2010) Naturally occurring food toxins. Toxins (Basel) 2(9):2289ā€“2332

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Driscoll JP, Yadav AS, Shah NR (2018) Role of glucuronidation and P450 oxidation in the bioactivation of Bromfenac. Chem Res Toxicol 31(4):223ā€“230

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Fleming TH, Humpert PM, Nawroth PP, Bierhaus A (2011) Reactive metabolites and AGE/RAGE- mediated cellular dysfunction affect the aging process: a mini-review. Gerontology 57(5):435ā€“443

    CASĀ  PubMedĀ  Google ScholarĀ 

  • Goetz ME, Luch A (2008) Reactive species: a cell damaging rout assisting to chemical carcinogens. Cancer Lett 266:73ā€“83

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Goldman JL, Koen YM, Rogers SA, Li K, Leeder JS, Hanzlik RP (2016) Bioactivation of trimethoprim to protein-reactive metabolites in human liver microsomes. Drug Metab Dispos 44(10):1603ā€“1607

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Gonzalez FJ (2005) Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 569:101ā€“110

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Goyer RA, Clarkson TW (2001) Toxic effects of metals. In: Klaasen CD (ed) Casarett and Doullis toxicology: the basic science of poisons, 6th edn. McGraw-Hill, New York, pp 861ā€“867

    Google ScholarĀ 

  • Haggerty HG, Kim BS, Holsapple MP (1990) Characterization of the effects of direct alkylators on in vitro immune responses. Mutat Res 242:67ā€“78

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Halliwell B (2007) Oxidative stress and cancer: have we moved forward? Biochem J 401(1):1ā€“11

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Hodgon E, Smart RC (2001) Introduction to biochemical toxicology. Wiley, New York

    Google ScholarĀ 

  • Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F (2018) Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol 100:1ā€“19

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Jaeschke H, Gores GJ, Cederbaum AI et al (2002) Mechanisms of hepatotoxicity. Toxicol Sci 65:166ā€“176

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Jan YH, Heck DE, Dragomir AC, Gardner CR, Laskin DL, Laskin JD (2014) Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol 27(5):882ā€“894

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Liebler DC, Guengerich FP (2005) Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 4(5):410ā€“420

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Liguori I, Russo G et al (2018) Oxidative stress, aging, and diseases. Clin Interv Aging 13:757ā€“772

    ArticleĀ  CASĀ  Google ScholarĀ 

  • LuĆ­s PB, Ruiter JP, Aires CC et al (2007) Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation. Biochim Biophys Acta 1767:1126ā€“1133

    ArticleĀ  Google ScholarĀ 

  • Masini A, Ceccarelli-Stanzani D et al (1985) The role of pentachlorophenol in causing mitochondrial derangement in hexachlorobenzene induced experimental porphyzria. Biochem Pharmacol 34:1171ā€“1174

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Mates JM (2000) Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 153:83ā€“104

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777:1249ā€“1262

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Perez MJ, Cederbaum AI (2003) Adenovirus-mediated expression of Cu/Zn- or Mn-superoxide dismutase protects against CYP2E1-dependent toxicity. Hepatology 38:1146ā€“1158

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Qu Q, Liu J, Zhou HH, Klaassen CD (2014) Nrf2 protects against furosemide-induced hepatotoxicity. Toxicology 324:35ā€“42

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Spracklin DK, Hankins DC, Fisher JM et al (1997) Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. J Pharmacol Exp Ther 281:400ā€“411

    CASĀ  PubMedĀ  Google ScholarĀ 

  • Thompson RA, Isin EM, Ogese MO, Mettetal JT, Williams DP (2016) Reactive metabolites: current and emerging risk and hazard assessments. Chem Res Toxicol 29(4):505ā€“533

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Tong V, Teng XW, Chang TK, Abbott FS (2005) Valproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes. Toxicol Sci 86:436ā€“443

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Turan B (2010) Role of antioxidants in redox regulation of diabetic cardiovascular complications. Curr Pharm Biotechnol 11(8):819ā€“836

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65ā€“74

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur IM (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):1ā€“40

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Vassort G, Turan B (2010) Protective role of antioxidants in diabetes-induced cardiac dysfunction. Cardiovasc Toxicol 10(2):73ā€“86

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Wani TH, Chakrabarty A, Shibata N, Yamazaki H, Guengerich FP, Chowdhury G (2017) The dihydroxy metabolite of the teratogen thalidomide causes oxidative DNA damage. Chem Res Toxicol 30(8):1622ā€“1628

    ArticleĀ  CASĀ  Google ScholarĀ 

  • Wells PG, Kim PM, Laposa RR et al (1997) Oxidative damage in chemical teratogenesis. Mutat Res 396:65ā€“78

    ArticleĀ  CASĀ  Google ScholarĀ 

  • West JD, Marnett LJ (2005) Alterations in gene expression induced by the lipid peroxidation product, 4-hydroxy-2-nonenal. Chem Res Toxicol 18:1642ā€“1653

    ArticleĀ  CASĀ  Google ScholarĀ 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

Ā© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chen, CH. (2020). Xenobiotic Bioactivation-Mediated Cellular Damages. In: Xenobiotic Metabolic Enzymes: Bioactivation and Antioxidant Defense. Springer, Cham. https://doi.org/10.1007/978-3-030-41679-9_12

Download citation

Publish with us

Policies and ethics