Application of Computational Chemistry in the Study of Biologically Reactive Intermediates

  • M. W. Anders
  • Hequn Yin
  • Jeffrey P. Jones
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


The toxicity of most xenobiotics is associated with their enzymatic conversion to toxic metabolites, a process termed bioactivation. Although stable, but toxic, metabolites may be formed, as in the biotransformation of dichloromethane to carbon monoxide, most bioactivation reactions afford electrophilic, reactive intermediates. The reactivity of these intermediates usually prevents their direct observation and characterization. Hence strategies that permit the experimentalist to gain insight into the formation and fate of reactive intermediates is of much value in understanding bioactivation reactions. The objective of this review is to point out the utility of computational chemistry in studying the formation and fate of toxic metabolites.


Quantum Chemical Method Allyl Alcohol Methyl Eugenol Molecular Mechanic Method Biotransformation Rate 
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  1. 1.
    Bowen, J. P., Charifson, P. S., Fox, P. C., Kontoyianni, M., Miller, A. B. Schnur, D., Stewart, E. L., Van Dyke, C., 1993, Computer-assisted molecular modeling: Indispensable tools for molecular pharmacology, J. Clin. Pharmacol, 33, 1149–1164.PubMedCrossRefGoogle Scholar
  2. 2.
    Andrianov, A. M., and Akhrem, A. A., 1993, Model of the spatial structure of peptide T, Molekuliarnai Biologiia 27, 934–946.Google Scholar
  3. 3.
    Goddard III, W. A., 1985, Theoretical chemistry comes alive: Full partner with experiment, Science 227, 917–923.PubMedCrossRefGoogle Scholar
  4. 4.
    Schaefer III, H. F., 1986, Methylene: A paradigm for computational quantum chemistry, Science 231, 1100–1107.PubMedCrossRefGoogle Scholar
  5. 5.
    Anders, M. W., 1991, Metabolism and toxicity of hydrochlorofluorocarbons: Current knowledge and needs for the future, Environ. Health Perspect. 96, 185–191.PubMedCrossRefGoogle Scholar
  6. 6.
    Korzekwa, K. R., Jones, J. P., and Gillette, J. R., 1990, Theoretical studies on cytochrome P-450 mediated hydroxylation: A predictive model for hydrogen atom abstractions, J. Am. Chem. Soc. 112, 7042–7046.CrossRefGoogle Scholar
  7. 7.
    Olson, M. J., Kim, S. G., Reidy, C. A., Johnson, J. T., and Novak, R. F., 1991, Oxidation of 1,1,1,2-tetrafluoroethane (R-134a) in rat liver microsomes is catalyzed primarily by cytochrome P450IIE1, Drug Metab. Dispos. 19, 298–303.PubMedGoogle Scholar
  8. 8.
    Herbst, J., Köster, U., Kerssebaum, R., and Dekant, W., 1994, Role of P4502E1 in the metabolism of l,1,2,2-tetrafluoro-l-(2,2,2-trifluoroethoxy)-ethane, Xenobiotica 24, 507–516.PubMedCrossRefGoogle Scholar
  9. 9.
    O’Hagan, D., and Rzepa, H. S., 1994, Stereospecific control of the citrate synthase mediated synthesis of (2R,3R)-3-fluorocitrate by the relative stabilities of the intermediate fluorocnolates, J. Chem. Soc, Chem. Commun. 1994, 2029–2030.CrossRefGoogle Scholar
  10. 10.
    Martin, D. P., Bibart, R. T., and Drueckhammer, D. G., 1994, Synthesis of novel analogs of acetyl coenzyme A: Mimics of enzyme reaction intermediates. J. Am. Chem. Soc. 116, 4660–4668.CrossRefGoogle Scholar
  11. 11.
    Tsai, R.-S., Carrupt, P.-A., Testa, B., and Caldwell, J., 1994, Structure-genotoxicity relationships of allylbenzenes and propenylbenzenes: A quantum chemical study, Chem. Res. Toxicol. 7, 73–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Hartung, R., 1982, Cyanide and nitriles, In Patty’s Industrial Hygiene and Toxicology (Patty, F. A., Clayton, G. D., and Clayton, F. E., Eds.) pp. 4845–4900, Interscience, New York.Google Scholar
  13. 13.
    Grogan, J., DeVito, S. C, Pearlman, R. S., and Korzekwa, K. R., 1992, Modeling cyanide release from nitriles: Prediction of cytochrome P450 mediated acute nitrile toxicity, Chem. Res. Toxicol. 5, 548–552.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • M. W. Anders
    • 1
  • Hequn Yin
    • 1
  • Jeffrey P. Jones
    • 1
  1. 1.Department of PharmacologyUniversity of RochesterRochesterUSA

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