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

• Published in: Xenobiotica 2002-07, Vol.32 (7), p.547-561
• Main Authors: Lewis, D. F. V., Lake, B. G.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; 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; Medical sciences; Mice; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Plant poisons toxicology; Quantitative Structure-Activity Relationship; Rats; Sequence Homology, Amino Acid; Species Specificity; Steroid Hydroxylases - chemistry; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Substrate Specificity; Thermodynamics; Toxicology
• ISSN: 0049-8254; 1366-5928
• 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.