Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a "Central Dogma" for Toxic Mechanisms?

  • Park, Yeong-Chul (GLP Center, Catholic University of Daegu) ;
  • Lee, Sundong (Dept. of Preventive Korean Medicine, School of Korean Medicine, Sangji University) ;
  • Cho, Myung-Haing (Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University)
  • Received : 2014.07.11
  • Accepted : 2014.09.18
  • Published : 2014.09.30
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Abstract

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

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References

  1. Evans, T.J. (2013) Small Animal Toxicology (Third Edition), Chapter 2 - Toxicokinetics and Toxicodynamics, Elsevier Publishing Company, pp. 13-19.
  2. Nagarkatti, P.S. and Nagarkatti, M. (1987) Immunotoxicology: Modulation of the immune system by xenobiotics. Def. Sci. J., 37, 235-244. https://doi.org/10.14429/dsj.37.5904
  3. Borzelleca, J.F. (2000) Profiles in toxicology. Paracelsus: herald of modern toxicology. Toxicol. Sci., 53, 2-4. https://doi.org/10.1093/toxsci/53.1.2
  4. International Agency for Research on cancer (IARC) Monograph. (2014) Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs. 1, 109.
  5. Betharia, S., Corcoran, G.B. and Ray, S.D. (2014) Mechanisms of Toxicity: In Encyclopedia of Toxicology (3rd Ed), Elsevier Publishing Company, pp. 165-175.
  6. Liska, D.J., Lyon, M. and Jones, D.S. (2006) Detoxification and biotransformation imbalance, Explore, 2, pp. 112-140.
  7. Gregus, Z. and Klaassen, C.D. (2008) Casarett & Doull's Toxicology (7th ed), The Basic Science of Poisons, Unit 1: Basic principle of toxicology, Chapter 3: mechanisms of toxicity, MC GRAW Hill, pp. 35-81.
  8. Attia, S.M. (2010) Deleterious effects of reactive metabolites. Oxid. Med. Cell. Longevity, 3, 238-253. https://doi.org/10.4161/oxim.3.4.13246
  9. Wells, P.G., Bhullera, Y., Chen, C.S., Jeng, W., Kasapinovic, S., Kennedy, J.C., Kim, P.M., Laposa, R.R., McCallum, G.P., Nicol, C.J., Parman, T., Wiley, M.J. and Wong, A.W. (2005) Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicol. Appl. Pharmacol., 207, 354-366. https://doi.org/10.1016/j.taap.2005.01.061
  10. Park, Y.C. (2010) The molecular and biochemical principles of toxicology. Korean studies Information Publishing Company, Korea, pp. 19-24.
  11. Kumar, V., Abba, A.K. and Aster, J.C. (2012) Robbins Basic Pathology (7th Edition), Elsevier, pp. 199-200.
  12. Working, P.K. (1989) Mechanistic Approaches in the Study of Testicular Toxicity: Agents that Directly Affect the Testis. Toxicol. Pathol., 17, 452-456. https://doi.org/10.1177/019262338901700221
  13. Ashauer, R., Hintermeister, A., O'Connor, I., Elumelu, M., Hollender, J. and Escher, B.I. (2012) Significance of xenobiotic metabolism for bioaccumulation kinetics of organic chemicals in gammarus pulex. Environ. Sci. Technol., 46, 3498-3508. https://doi.org/10.1021/es204611h
  14. Liska, D.J. (1998) The Detoxification Enzyme Systems. Altern. Med. Rev., 3. 187-198.
  15. Kumar, G.N. and Surapaneni, S. (2001) Role of drug metabolism in drug discovery and development. Med. Res. Rev., 21, 397-411. https://doi.org/10.1002/med.1016
  16. Schroer, K., Kittelmann, M. and Lutz, S. (2010) Recombinant human cytochrome P450 monooxygenases for drug metabolite synthesis. Biotechnol. Bioeng., 106, 699-706. https://doi.org/10.1002/bit.22775
  17. Guengerich, F.P. (2006) Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J., 8, E101-E111. https://doi.org/10.1208/aapsj080112
  18. Zanger, U.M. and Schwab, M. (2013) Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 138, 103-141. https://doi.org/10.1016/j.pharmthera.2012.12.007
  19. Orhan, H. and Vermeulen, N.P. (2011) Conventional and novel approaches in generating and characterization of reactive intermediates from drugs/drug candidates. Curr. Drug Metab., 12, 383-394. https://doi.org/10.2174/138920011795202974
  20. Bertz, R.J. and Granneman, G.R. (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin. Pharmacokinet., 32, 210-258. https://doi.org/10.2165/00003088-199732030-00004
  21. Yan, Z. and Caldwell, G.W. (2001) Metabolic profiling, and cytochrome P450 inhibition &induction in drug discovery. Curr. Top. Med. Chem., 1, 403-425. https://doi.org/10.2174/1568026013395001
  22. Srivastava, A., Maggs, J.L., Antoine, D.J., Williams, D.P., Smith, D.A. and Park, B.K. (2010) Role of reactive metabolites in drug-induced hepatotoxicity. Handb. Exp. Pharmacol., 196, 165-194. https://doi.org/10.1007/978-3-642-00663-0_7
  23. Bolton, J.L., Trush, M.A., Penning, T.M., Dryhurst, G. and Monks, T.J. (2000) Role of quinones in toxicology. Chem. Res. Toxicol., 13, 135-160. https://doi.org/10.1021/tx9902082
  24. Lopachin, R.M. and Decaprio, A.P. (2005) Protein Adduct Formation as a Molecular Mechanism in Neurotoxicity. Toxicol. Sci., 86, 214-225. https://doi.org/10.1093/toxsci/kfi197
  25. Nioi, P. and Hayes, J.D. (2004) Contribution of NAD(P)H: quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loophelix transcription factors. Mutat. Res., 555, 149-171. https://doi.org/10.1016/j.mrfmmm.2004.05.023
  26. Guengerich, F.P. (1992) Metabolic activation of carcinogens. Pharmacol. Ther., 54, 17-61. https://doi.org/10.1016/0163-7258(92)90050-A
  27. Goetz, M.E. and Luch, A. (2008) Reactive species: A cell damaging rout assisting to chemical carcinogens. Cancer Lett., 266, 73-83. https://doi.org/10.1016/j.canlet.2008.02.035
  28. Gram, T.G. (1997) Chemically reactive intermediates and pulmonary xenobiotic toxicity. Pharmacol. Rev., 49, 297-341.
  29. Tolando, R., Zanovello, A., Ferrara, R., Iley, J.N. and Manno, M. (2001) Inactivation of rat liver cytochrome P450 (P450) by N,N-dimethylformamide and N,N-dimethylacetamide. Toxicol. Lett., 124, 101-111. https://doi.org/10.1016/S0378-4274(01)00384-8
  30. Well, P.G., Kim, P.M., Nicol, C.J., Parman, T. and Winn, LM. (1997) Drug Toxicity in Embryonic Development I; Reactive Intermediates. Springer Berlin Heidelberg Publishing Company, 124, 453-518.
  31. Gold, B., Marky, L.M., Stone, M.P. and Williams, L.D. (2006) A review of the role of the sequence-dependent electrostatic landscape in DNA Aakylation patterns. Chem. Res. Toxicol., 19, 1402-1414. https://doi.org/10.1021/tx060127n
  32. Shu, Y.Z., Johnson, B.M. and Yang, T.J. (2008) Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery. AAPS J., 10, 178-192. https://doi.org/10.1208/s12248-008-9016-9
  33. van Bladeren, P.J. (2000) Glutathione conjugation as a bioactivation reaction. Chem. Biol. Interact., 129, 61-76. https://doi.org/10.1016/S0009-2797(00)00214-3
  34. Masubuchi, N., Makino, C. and Murayama, N. (2007) Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans. Chem. Res. Toxicol., 20, 455-464. https://doi.org/10.1021/tx060234h
  35. Djurovic, J. (2012) Biotransformation of the toxic chemical substances. Math. Models Methods Appl. Sci., 91-95.
  36. Smith, M.T., Yager, J.W., Steinmetz, K.L. and Eastmondt, D.A. (1989) Peroxidase-dependent metabolism of benzene's phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environ. Health Perspect., 82, 23-29. https://doi.org/10.1289/ehp.898223
  37. Glatt, H. (2000) Sulfotransferases in the bioactivation of xenobiotics. Chem. Biol. Interact., 129, 141-170. https://doi.org/10.1016/S0009-2797(00)00202-7
  38. Guengerich, F.P. and Shimada T. (1998) Activation of procarcinogens by human cytochrome P450 enzymes. Mutat. Res., 400, 201-213. https://doi.org/10.1016/S0027-5107(98)00037-2
  39. Ashauer, R. and Escher, B.I. (2010) Advantages of toxicokinetic and toxicodynamic modeling in aquatic ecotoxicology and risk assessment. J. Environ. Monit., 12, 2056-2061. https://doi.org/10.1039/c0em00234h
  40. Crick, F. (1970) Central dogma of molecular biology. Nature, 227, 561-563. https://doi.org/10.1038/227561a0
  41. Thieffry, D. and Sarkar, S. (1998) Forty years under the central dogma. Trends Biochem. Sci., 23, 312-316. https://doi.org/10.1016/S0968-0004(98)01244-4
  42. Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am., 291, 60-67. https://doi.org/10.1038/scientificamerican1004-60

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