Species differences in coumarin metabolism: a molecular modelling evaluation of CYP2A interactions

Xenobiotica. 2002 Jul;32(7):547-61. doi: 10.1080/00498250210128693.


1. An account of the differences in coumarin metabolism between several mammalian species, including man, is reported. 2. The metabolism of coumarin via 7-hydroxylation in the human (CYP2A6) and mouse (CYP2A5) enzymes is explained in terms of molecular modelling of the active site interactions, whereas the rat orthologue (CYP2A1) exhibits 3,4-epoxidation of coumarin, which is also consistent with the modelled interaction between enzyme and substrate. 3. In addition, quantitative structure-activity relationships (QSARs) for coumarin 7-hydroxylation in wild-type and mutant CYP2A5 show the importance of amino acid residue properties for substrate binding, whereas QSARs for CYP2A6 substrates indicate the importance of hydrogen bonding and lipophilicity for favourable interactions with the enzyme.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Catalytic Domain
  • Coumarins / metabolism*
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochrome P450 Family 2
  • Humans
  • Hydrogen Bonding
  • Mice
  • Mixed Function Oxygenases / chemistry*
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Quantitative Structure-Activity Relationship
  • Rats
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Steroid Hydroxylases / chemistry*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*
  • Substrate Specificity
  • Thermodynamics


  • Coumarins
  • Cytochrome P-450 Enzyme System
  • coumarin
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cyp2a5 protein, mouse
  • Cytochrome P-450 CYP2A6
  • Cytochrome P450 Family 2
  • testosterone 7-alpha-hydroxylase, hamster