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

Publisher: Informa Healthcare Country of Publication: England NLM ID: 1306665 Publication Model: Print Cited Medium: Print ISSN: 0049-8254 (Print) Linking ISSN: 00498254 NLM ISO Abbreviation: Xenobiotica Subsets: MEDLINE

Publication: London : Informa Healthcare
Original Publication: London, Taylor & Francis.

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

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.

0 (Coumarins)
9035-51-2 (Cytochrome P-450 Enzyme System)
A4VZ22K1WT (coumarin)
EC 1.- (Mixed Function Oxygenases)
EC 1.14.- (Steroid Hydroxylases)
EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
EC 1.14.14.1 (CYP2A6 protein, human)
EC 1.14.14.1 (Cyp2a5 protein, mouse)
EC 1.14.14.1 (Cytochrome P-450 CYP2A6)
EC 1.14.14.1 (Cytochrome P450 Family 2)
EC 1.14.14.1 (testosterone 7-alpha-hydroxylase, hamster)

Date Created: 20020807 Date Completed: 20020916 Latest Revision: 20190910

20250114

10.1080/00498250210128693

12162851