A predictive model for substrates of cytochrome P450-debrisoquine (2D6)

L. Koymans, N P E Vermeulen, S.A.B.E. van Acker, J.M. te Koppele, J J P Heykants, K Lavrijsen, W Meuldermans, G M Donné-Op den Kelder

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Abstract

Molecular modeling techniques were used to derive a predictive model for substrates of cytochrome P450 2D6, an isozyme known to metabolize only compounds with one or more basic nitrogen atoms. Sixteen substrates, accounting for 23 metabolic reactions, with a distance of either 5 A ("5-A substrates", e.g., debrisoquine) or 7 A ("7-A substrates", e.g., dextromethorphan) between oxidation site and basic nitrogen atom were fitted into one model by postulating an interaction of the basic nitrogen atom with a negatively charged carboxylate group on the protein. This acidic residue anchors and neutralizes the positively charged basic nitrogen atom of the substrates. In case of "5-A substrates" this interaction probably occurs with the carboxylic oxygen atom nearest to the oxidation site, whereas in the case of "7-A substrates" this interaction takes place at the other oxygen atom. Furthermore, all substrates exhibit a coplanar conformation near the oxidation site and have negative molecular electrostatic potentials (MEPs) in a part of this planar domain approximately 3 A away from the oxidation site. No common features were found in the neighbourhood of the basic nitrogen atom of the substrates studied so that this region of the active site can accommodate a variety of N-substituents. Therefore, the substrate specificity of P450 2D6 most likely is determined by the distance between oxidation site and basic nitrogen atom, by steric constraints near the oxidation site, and by the degree of complementarity between the MEPs of substrate and protein in the planar region adjacent to the oxidation site.(ABSTRACT TRUNCATED AT 250 WORDS)

Original languageEnglish
Pages (from-to)211-219
Number of pages9
JournalChemical Research in Toxicology
Volume5
Issue number2
DOIs
Publication statusPublished - 1 Mar 1992

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Keywords

  • Astemizole
  • Binding Sites
  • Cells, Cultured
  • Computer Simulation
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 Enzyme System
  • Debrisoquin
  • Female
  • Humans
  • Isoenzymes
  • Isoxazoles
  • Male
  • Microsomes, Liver
  • Mixed Function Oxygenases
  • Models, Molecular
  • Piperidines
  • Risperidone
  • Substrate Specificity
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Koymans, L., Vermeulen, N. P. E., van Acker, S. A. B. E., te Koppele, J. M., Heykants, J. J. P., Lavrijsen, K., ... Donné-Op den Kelder, G. M. (1992). A predictive model for substrates of cytochrome P450-debrisoquine (2D6). Chemical Research in Toxicology, 5(2), 211-219. https://doi.org/10.1021/tx00026a010