Receptor Mediated Toxicity: The Dioxin Receptor as an Example of Biological Complexity and Experimental Approaches

  • Thomas R. Sutter
  • Chris W. Cody
  • Jonathan A. Gastel
  • Carrie L. Hayes
  • Ying Li
  • Nigel J. Walker
  • Hong Yin
Conference paper
Part of the NATO ASI Series book series (volume 93)


During the past decade tremendous advances have been made in understanding the role of receptors as signal transducers, linking cells and their environment in a carefully orchestrated symphony of multicellular life. Through changes in gene expression, receptors facilitate a multitude of complex biological responses including differentiation, mitosis, apoptosis, and quiescence. While the mechanics of receptor activation and subsequent enhancement of transcription have yielded to modern methods of pharmacology and molecular biology, less progress has been made towards understanding causal relationships between changes in gene expression and cellular and tissue responses. Like other critical cellular targets, receptor proteins provide specific, high affinity sites for chemical interaction. In some cases, such chemical interactions have defined the action of receptors in the absence of any knowledge of their endogenous ligand or function. The dioxin receptor is one such example that illustrates both the biological complexity of, and experimental approaches to understanding receptor mediated toxicity.


Aldehyde Dehydrogenase Organohalogen Compound Human Keratinocyte Cell Line Intracellular Communication Cell BioI 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Asman DC, Koichi T, Pitot HC, Dunn TJ, Lindahl R (1993) Organization and characterization of the rat class 3 aldehyde dehydrogenase gene. J Biol Chem 268: 12530–12536PubMedGoogle Scholar
  2. Burbach KM, Poland A and Bradfield CA (1992) Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci 89: 8185–8189PubMedCrossRefGoogle Scholar
  3. Castagna M (1987) Phorbol esters as signal transducers and tumor promoters. Biol of the Cell 59: 3–14Google Scholar
  4. Choi EJ, Toscano DG, Ryan JA, Riedel N, Toscano Jr WA (1991) Dioxin induces transforming growth factor-α in human keratinocytes. J Biol Chem 266: 9591–9597PubMedGoogle Scholar
  5. Clark AR and Docherty K (1993) Negative regulation of transcription in eukaryotes. Biochem J 296: 521–541PubMedGoogle Scholar
  6. Conney AH (1967) Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366PubMedGoogle Scholar
  7. Cross M and Dexter TM (1991) Growth factors in development, transformation, and tumorigenesis. Cell 64: 271–280PubMedCrossRefGoogle Scholar
  8. Edwards DR (1994) Cell signalling and the control of gene transcription. Trends in Pharmacol Sci 15: 239–244CrossRefGoogle Scholar
  9. Fuller P (1991) The steriod receptor superfamily: mechanisms of diversity. FASEB J 5: 3092–3099PubMedGoogle Scholar
  10. Gaido KW, Maness SC, Leonard LS and Greenlee WF (1992) 2,3,7,8- Tetrachlorodibenzo-p-dioxin-dependent regulation of transforming growth factors- α and–β2 expression in a human keratinocyte cell line involves both transcriptional and post-transcriptional control. J Biol Chem 267: 24591–24595Google Scholar
  11. Glass CK (1994) Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocrine Reviews 15: 391–407PubMedGoogle Scholar
  12. Greco TL, Duello TM, and Gorski J (1993) Estrogen receptors, estradiol, and diethylstilbestrol in early development: the mouse as a model for the study of estrogen receptors and estrogen sensitivity in embryonic development of male and female reproductive tracts. Endocrine Reviews 14: 59–71PubMedGoogle Scholar
  13. Green S (1992) Nuclear receptors and chemical carcinogenesis. Trends in Pharmacol Sci 13: 251–255CrossRefGoogle Scholar
  14. Greenlee WF, Osborne R, Dold KM, Ross L and Cook JC (1987) TCDD: mechanisms of altered growth regulation in human epidermal keratinocytes. Banbury Report 25: Nongenotoxic mechanisms in carcinogenesis 25: 247–255Google Scholar
  15. Greenlee WF, Osborne R and Dold KM (1987b) Altered regulation of epidermal cell proliferation and differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD ). Rev Biochem Toxicol 8: 1–35Google Scholar
  16. Greenlee WF, Sutter, TR and Marcus C (1994) Molecular basis of dioxin action on rodent and human target tissues. In Receptor-Mediated Biological Processes: Implications for Evaluating Carcinogenesis, Spitzer HL, Slaga, TJ, Greenlee WF, McClain M (eds) Recent Prog Clin and Biol Res, Wiley-Liss, Vol 387, pp. 47–57Google Scholar
  17. Gudas LJ (1992) Retinoids, retinoid-responsive genes, cell differentiation, and cancer. Cell Growth and Differentiation 3: 655–662PubMedGoogle Scholar
  18. Guilarte TR, Miceli RC, Altmann L, Weinsberg F, Winneke G and Wiegand H (1993) Chronic prenatal and postnatal Pb2+ exposure increases [3H]MK801 binding sites in adult rat forebrain. Eur J Pharmacol-Environ Toxicol and Pharmacol Section 248: 273–275CrossRefGoogle Scholar
  19. Gusousky F, Daly JW, (1990) Maitotoxin: A Unique Pharmacological Tool for Research in Calcium Dependent Mechanisms, Biochem. Pharm. 39(11): 1633–9CrossRefGoogle Scholar
  20. Hoffman BF, Bigger JT (1990) Digitalis and Allied Cardiac Glycosides. In The Pharmacological Basis of Therapeutics, Goodman Gilman A, Rail T, Nies A, and Taylor P (eds), Pergamon Press, New York, pp. 814–840Google Scholar
  21. Huff JE, Salmon AG, Hooper NK and Zeise L (1991) Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p- dioxins. Cell Biol and Toxicol 7: 67–94CrossRefGoogle Scholar
  22. Hunt P and Krumlauf R (1992) HOX codes and positional specification in vertebrate embryonic axes. Annu Rev Cell Biol 8: 227–256PubMedCrossRefGoogle Scholar
  23. Johnson, ES (1993) Important aspects of the evidence for TCDD carcinogenicity in man. Environ Health Perspect 99: 383–390PubMedCrossRefGoogle Scholar
  24. Jones PBC, Galeazzi DR, Fisher JM and Whitlock JP, Jr (1985) Control of cytochrome Pi-450 gene expression by dioxin. Science 227: 1499–1502PubMedCrossRefGoogle Scholar
  25. Kao CY and Levinson SR (eds) (1986) Tetrodotoxin, Saxitoxin, and the molecular biology of sodium channel. Annals of New York Acad. Sci. Vol 479Google Scholar
  26. Katzenellenbogen BS, Bhardwaj B, Fang H, Ince BA, Pakdel F, Reese JC, Schodin D and Wrenn CK (1993) Hormone binding and transcription activation by estrogen receptors: analyses using mammalian and yeast systems. J Steriod Biochem Molec Biol 47: 39–48CrossRefGoogle Scholar
  27. Kuhar MJ, Ritz MC, Sharkey J, (1988) Cocaine Receptors on Dopamine Transporters Mediate Cocaine-Reinforced Behavior, in Mechanisms of Cocaine Abuse and Toxicity, Clouet D, Khurseed A, Brown R (eds) NIDA Res. Monograph, vol. 88Google Scholar
  28. Madshus IH and Stenmark H (1992) Entry of ADP-ribosylating toxins into cells. Current Topics in Microbiol and Immunol 175: 1–26Google Scholar
  29. Nebert DW (1989) The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. Crit Rev Toxicol 20: 153–174PubMedCrossRefGoogle Scholar
  30. Nebert DW (1991) Proposed role of drug-metabolizing enzymes: Regulation of steady state levels of the ligands that effect growth, homeostasis, differentiation, and neuroendocrine functions. Mol Endocrinol 5: 1203–1214PubMedCrossRefGoogle Scholar
  31. Nebert DW (1994) Drug-metabolizing enzymes in ligand-modulated transcription. Biochem Pharmacol 47: 25–37PubMedCrossRefGoogle Scholar
  32. Nebert DW and Gonzalez FJ (1987) P450 genes: structure, evolution and regulation. Annu Rev Biochem 56: 945–993PubMedCrossRefGoogle Scholar
  33. Nebert DW, Goujan FM, Gielen, JE (1972) Aryl hydrocarbon hydroxyalse induction by polycyclic hydrocarbons: simple autosomal dominant trait in the mouse. Nature 236: 107–110Google Scholar
  34. Okey AB (1990) Enzyme induction in the cytochrome P-450 system. Pharmac Ther 45: 241–298CrossRefGoogle Scholar
  35. Olson EN, Burgess R and Staudinger J (1993) Protein kinase C as a transducer of nuclear signals. Cell Growth and Differentiation 4: 699–705PubMedGoogle Scholar
  36. Orti E, Bodwell JE and Munck A (1992) Phosphorylation of steroid hormone receptors. Endocrine Reviews 13: 105–128PubMedGoogle Scholar
  37. Poland A and Knutson JC (1982) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Ann Rev Pharmacol Toxicol 22:517–554CrossRefGoogle Scholar
  38. Poland A, Glover E (1976) Stereospecific, high affinity binding of 2,3,7,8- tetrachlorodibenzo-p-dioxin by hepatic cytosol. J Biol Chem 251: 4936–4946PubMedGoogle Scholar
  39. Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, Fletcher SR, Iversen LL, and Broughton HB (1994) Mechanism of inositol monophosphatase, the putative target of lithium therapy. Proc Natl Acad Sci USA 91: 5766–5770PubMedCrossRefGoogle Scholar
  40. Quattrochi LC, Vu T and Tukey RH (1994) The human CYP1A2 gene and induction by 3-methylcholanthrene. J Biol Chem 269: 6949–6954PubMedGoogle Scholar
  41. Reyes H, Reisz-Porszasz S and Hankinson O (1992) Identification of the Ah receptor nuclear translocator protein ( Arnt) as a component of the DNA binding form of the Ah receptor. Science 256: 1193–1195Google Scholar
  42. Safe S(1990) Polychlorinated biphenyls, dibenzo-p-dioxins, dibenzofurans, and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors. Crit Rev Toxicol 21:51–88PubMedCrossRefGoogle Scholar
  43. Savas U, Bhattacharyya KK, Christou M, Alexander DL and Jefcoate CR (1994) Mouse cytochrome P-450EF, representative of a new IB subfamily of cytochrome P-450s. J Biol Chem 269: 14905–14911PubMedGoogle Scholar
  44. Sekura R, Moss J, Vaughan M (eds) (1985) Pertusis Toxinz Academic Press, Orlando, FL, pp. 1–251Google Scholar
  45. Serventi IM, Moss J and Vaughan M (1992) Enhancement of cholera toxin- catalyzed ADP-ribosylation by guanine nucleotide-binding proteins. Current Topics in Microbiol and Immunol 175: 43–67Google Scholar
  46. Shen ES and Whitlock JP, Jr (1992) Protein-DNA interactions at a dioxin- responsive enhancer. J Biol Chem 267: 6815–6819PubMedGoogle Scholar
  47. Snyder SH, Chang KJ, Kuhar MJ, Yamamura HI (1975) Biochemical Identification of the Mammalian Muscarinic Cholinergic Receptor, Fed. Proc. 34 (10): 1915–21PubMedGoogle Scholar
  48. Spink DC, Hayes CL, Young NR, Christou M, Sutter TR, Jefcoate CR and Gierthy JF (1994) The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estrogen metabolism in MCF-7 breast cancer cells: Evidence for induction of a novel 17β-estradiol 4-hydroxylase. J Steroid Biochem Molec Biol, in press.Google Scholar
  49. Stahl BU, Beer DG, Weber LWD and Rozman K (1993) Reduction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity by 2,3,7,8- tetrachlorodibenzo-p-dioxin ( TCDD) is due to decreased mRNA levels. Toxicology 79: 81–95PubMedCrossRefGoogle Scholar
  50. Sutter TR and Greenlee WF (1992) Classification of members of the Ah gene battery. Chemosphere 25: 223–226CrossRefGoogle Scholar
  51. Sutter TR and Greenlee WF (1992b) Identification of a human dioxin-responsive cDNA (clone 1) as a new member of the cytochrome P450 superfamily. Organohalogen Compounds 10: 221–224Google Scholar
  52. Sutter TR, Andersen ME, Corton JC, Gaido K, Guzman K and Greenlee WF (1991) Development of a molecular basis for dioxin risk assessment in humans. Banbury Report 35: Biological basis for risk assessment of dioxins and related compounds 35: 379–388Google Scholar
  53. Sutter TR, Guzman K, Dold KM and Greenlee WF (1991b) Targets for dioxin:genes for plasminogen activator inhibitor-2 and interleukin-1β. Science 254: 415–418PubMedCrossRefGoogle Scholar
  54. Sutter TR, Tang YM, Hayes CL, Wo Y-YP, Jabs EW, Li X, Yin H, Cody CW and Greenlee WF (1994) Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. J Biol Chem 269: 13092–13099PubMedGoogle Scholar
  55. Swanson HI and Bradfield CA (1993) The Ah-receptor: genetics, structure and function. Pharmacogenetics 3: 213–230PubMedCrossRefGoogle Scholar
  56. Takimoto K, Lindahl R and Pitot HC (1992) Regulation of 2,3,7,8- tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase in hepatoma cells. Arch Biochem Biophys 298: 492–497CrossRefGoogle Scholar
  57. Uteshev V, Busselberg D and Haas HL (1993) Pb2+ modulates the NMDA- receptor-channel complex. Naunyn Schmiedebergs Arch Pharmacol 347: 209–213PubMedCrossRefGoogle Scholar
  58. Walters MR (1992) Newly identified actions of the vitamin D endocrine system. Endocrine Reviews 13: 719–764PubMedGoogle Scholar
  59. Weinstein IB (1991) Nonmutagenic mechanisms in carcinogenesis: role of protein kinase C in signal transduction and growth control. Environ Health Perspect 93: 175–179PubMedCrossRefGoogle Scholar
  60. Whitlock JP, Jr (1993) Mechanistic aspects of dioxin action. Chem Res Toxicol 6: 754–763PubMedCrossRefGoogle Scholar
  61. Wilhelmsson A, Cuthill S, Denis M, Wikstrom, A-C, Gustafsson J-A, and Poellinger L (1990) The specific DNA binding activity of the dioxin receptor is modulated by the 90kd heat shock protein. EMBO J 9: 69–76PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • Thomas R. Sutter
    • 1
  • Chris W. Cody
    • 1
  • Jonathan A. Gastel
    • 1
  • Carrie L. Hayes
    • 1
  • Ying Li
    • 1
  • Nigel J. Walker
    • 1
  • Hong Yin
    • 1
  1. 1.Department of Environmental Health Sciences, Division of Toxicological SciencesJohns Hopkins University, School of Hygiene and Public HealthBaltimoreUSA

Personalised recommendations