Target-Organ Toxicity: Liver and Kidney

  • Philip C. Burcham


Accidental or deliberate overdose with the analgesic paracetamol can cause life-threatening liver damage. Likewise, extensive use of nonsteroidal anti-inflammatory drugs such as ibuprofen causes kidney damage in vulnerable patients (e.g. the elderly). In addition to these medicinal risks, liver and kidney damages accompany exposure to synthetic chemicals in the workplace or as environmental pollutants. Still other chemicals that harm the excretory organs are consumed as food contaminants. The vulnerability of the liver and kidney to xenobiotic toxicity raises the question as to why such chemicals often display ‘organ selectivity’ when inducing toxicity. This chapter explores the factors that render the liver and kidney susceptible to toxicity, while also surveying typical toxic responses in these organs (e.g. steatosis, fibrosis, cancer). The diverse mechanisms underlying excretory organ toxicity are illustrated for such classic toxicants as azidothymidine, carbon tetrachloride, paracetamol, troglitazone, cylindrospermopsin and trichloroethylene.


Target-organ toxicity Hepatotoxicity Fatty liver (steatosis) Cholestasis Liver fibrosis Paracetamol Azidothymidine Troglitazone Carbon tetrachloride Thioacetamide Aflatoxin B1 Cylindrospermopsin Microcystin-LR Nephrotoxicity Aminoglycosides Chloroform Trichloroethylene 

Going Further

  1. Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis. 2013;17:191–209.PubMedCrossRefGoogle Scholar
  2. Corsini A, Bortolini M. Drug-induced liver injury: the role of drug metabolism and transport. J Clin Pharmacol. 2013;53:463–74.PubMedCrossRefGoogle Scholar
  3. Flajs D, Peraica M. Toxicological properties of citrinin. Arch Ind Hyg Toxicol. 2009;60:457–64.Google Scholar
  4. Fromenty B. Bridging the gap between old and new concepts in drug-induced liver injury. Clin Res Hepatol Gastroenterol. 2013;37:6–9.PubMedCrossRefGoogle Scholar
  5. Griffiths DJ, Saker ML. The Palm Island mystery disease 20 years on: a review of research on the cyanotoxin cylindrospermopsin. Environ Toxicol. 2003;18:78–93.PubMedCrossRefGoogle Scholar
  6. Guengerich FP. Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation. Arch Biochem Biophys. 2005;433:369–78.PubMedCrossRefGoogle Scholar
  7. Hosohata K et al. Urinary vanin-1 as a novel biomarker for early detection of drug-induced acute kidney injury. J Pharmacol Exp Ther. 2012;341:656–62.PubMedCrossRefGoogle Scholar
  8. Ikeda T. Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. Drug Metab Pharmacokinet. 2011;26:60–70.PubMedCrossRefGoogle Scholar
  9. Jones M, Núñez M. Liver toxicity of antiretroviral drugs. Semin Liver Dis. 2012;32:167–76.PubMedCrossRefGoogle Scholar
  10. Koen YM, et al. Protein targets of thioacetamide metabolites in rat hepatocytes. Chem Res Toxicol. 2013. PMID: 23465048. Epub2013 Mar 20.Google Scholar
  11. Lacquaniti A et al. Hydrocarbons and kidney damage: potential use of neutrophil gelatinase-associated lipocalin and sister chromatide exchange. Am J Nephrol. 2012;35:271–8.PubMedCrossRefGoogle Scholar
  12. Lash LH, et al. Metabolism of trichloroethylene. Environ Health Perspect. 2000;108(Suppl. 2):177–200.Google Scholar
  13. Leung GP. Iatrogenic mitochondriopathies: a recent lesson from nucleoside/nucleotide reverse transcriptase inhibitors. Adv Exp Med Biol. 2012;942:347–69.PubMedCrossRefGoogle Scholar
  14. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug MetabToxicol. 2006;2:493–503.CrossRefGoogle Scholar
  15. López-alonso H et al. Protein synthesis inhibition and oxidative stress induced by cylindrospermopsin elicit apoptosis in primary rat hepatocytes. Chem Res Toxicol. 2013;26:203–12.PubMedCrossRefGoogle Scholar
  16. Park KB et al. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol. 2005;45:177–202.PubMedCrossRefGoogle Scholar
  17. Prozialeck WC et al. Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney Int. 2007;72:985–93.PubMedCrossRefGoogle Scholar
  18. Rouse R et al. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat. PLoS One. 2012;7(4):e34606. doi: 10.1371/journal.pone.0034606. Epub 2012 Apr 11.PubMedCrossRefGoogle Scholar
  19. Rusyn I et al. Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard. Pharmacol Ther. 2013; pii: S0163-7258(13)00180-0. doi:  10.1016/j.pharmthera.2013.08.004. Epub 2013 Aug 23.
  20. Schnellmann RG, Kelly KJ. Pathophysiology of nephrotoxic acute renal failure, Chapter 15. In: Schrier RW, editor. Atlas of diseases of the kidney, vol. 1. Philadelphia: Current Medicine; 1999.Google Scholar
  21. Svircev Z et al. Molecular aspects of microcystin-induced hepatotoxicity and hepatocarcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2010;28:39–59.PubMedCrossRefGoogle Scholar
  22. Swain A et al. Nephrotoxicity of hexachloro-1:3-butadiene in the male Hanover Wistar rat; correlation of minimal histopathological changes with biomarkers of renal injury. J Appl Toxicol. 2012;32:417–28.PubMedCrossRefGoogle Scholar
  23. Thomson JS, Prescott LF. Liver damage and impaired glucose tolerance after paracetamol overdosage. Br Med J. 1966;2(5512):506–7.PubMedCrossRefGoogle Scholar
  24. Vermeulen R et al. Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene. Carcinogenesis. 2012;33:1538–41.PubMedCrossRefGoogle Scholar
  25. Zhang L et al. Identification of identical transcript changes in liver and whole blood during acetaminophen toxicity. Front Genet. 2012;3:162. doi: 10.3389/fgene.2012.00162. Epub 2012 Sep 4.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Philip C. Burcham
    • 1
  1. 1.School of Medicine and PharmacologyThe University of Western AustraliaPerthAustralia

Personalised recommendations