Fight Back: Adaptive Responses to Toxicant Exposure

  • Philip C. Burcham


The popularity of barbiturate sedatives in bygone days helped physicians discover an unusual property of these medicines: on repeated use, patients experienced a dramatic loss of effectiveness, with higher and higher doses required to elicit the original drug response. This capacity for physical tolerance alerted researchers to the phenomenon of enzyme induction: upon sustained exposure, the liver and other tissues simultaneously boost the expression of enzymes that convert xenobiotics to water-soluble metabolites and membrane transporters that expel metabolites via bile or urine. These outcomes reflect the actions of xenosensors – bifunctional proteins that detect ingested xenobiotics and then activate broad transcriptional responses that facilitate their clearance from the body. While such adaptive changes protect the body by altering the toxicokinetic fate of xenobiotics, transcriptional changes also occur at the subcellular level to protect tissues against cell-damaging reactive metabolites. Upon detecting cell or protein damage caused by electrophiles, cells mount strong transcriptional responses to suppress the toxicodynamic properties of xenobiotics via a number of pathways including the heat shock response, the antioxidant response, the unfolded protein response and the NFkB pathway.


Induction Xenosensors Pregnane X receptor (PXR) Aryl hydrocarbon receptor (AhR) Constitutive androstane receptor (CAR) Peroxisome proliferator-activated receptor (PPAR) Antioxidant response Nrf2 Endoplasmic reticulum stress Unfolded protein response Heat shock proteins Heat shock factor-1 NFkB 

Going Further

  1. Agostinis P, Afshin S, editors. Endoplasmic reticulum stress in health and disease. Dordrecht: Springer Science and Business Media; 2012.Google Scholar
  2. Anckar J, Sistonen L. Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem. 2011;80:1089–115.PubMedCrossRefGoogle Scholar
  3. Bataille AM, Manautou JE. Nrf2: a potential target for new therapeutics in liver disease. Clin Pharmacol Ther. 2012;92:340–8.PubMedCrossRefGoogle Scholar
  4. Boutros PC, et al. Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity. Toxicol Appl Pharmacol. 2011;251:119–29.PubMedCrossRefGoogle Scholar
  5. Cyr DM, Hebert DN. Protein quality control–linking the unfolded protein response to disease. EMBO Rep. 2009;10:1206–10.PubMedCrossRefGoogle Scholar
  6. Gonzalez FJ. Nuclear receptor control of enterohepatic circulation. Compr Physiol. 2012;2:2811–28.PubMedGoogle Scholar
  7. Gu X, Manautou JE. Regulation of hepatic ABCC transporters by xenobiotics and in disease states. Drug Metab Rev. 2010;42:482–538.PubMedCrossRefGoogle Scholar
  8. Hukkanen J. Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Rev Clin Pharmacol. 2012;5:569–85.PubMedCrossRefGoogle Scholar
  9. Ihunnah CA, et al. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta. 2011;1812:956–63.PubMedCrossRefGoogle Scholar
  10. Kensler TW, et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis. 2012;33:101–7.PubMedCrossRefGoogle Scholar
  11. Okey AB. An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. Toxicol Sci. 2007;98:5–38.PubMedCrossRefGoogle Scholar
  12. Peters JM, et al. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer. 2012;12:181–95.PubMedGoogle Scholar
  13. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12:564–71.PubMedCrossRefGoogle Scholar
  14. Staud F, et al. Expression and function of p-glycoprotein in normal tissues: effect on pharmacokinetics. Methods Mol Biol. 2010;596:199–222.PubMedCrossRefGoogle Scholar
  15. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6.PubMedCrossRefGoogle Scholar
  16. West JD, Marnett LJ. Endogenous reactive intermediates as modulators of cell signaling and cell death. Chem Res Toxicol. 2006;19:173–94.PubMedCrossRefGoogle 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