Molecular modelling of CYP2F substrates: comparison of naphthalene metabolism by human, rat and mouse CYP2F subfamily enzymes.
We have constructed three-dimensional molecular models of some cytochrome P450 (CYP) CYP2F subfamily forms via homology with CYP2C5 where sequence identities are in the region of 55%, thus representing high degrees of confidence in the accuracy of the models produced. The three-dimensional structures of these CYP2F enzymes have been compared by molecular overlay, especially with regard to the active site regions, and it would appear that the substitution of a lysine (Lys-301) in human CYP2F1 for the usual glutamate (Glu-301) in mouse CYP2F2, goat CYPF3 and rat CYP2F4 prior to the conserved distal threonine residue may well constitute a significant factor in any species differences between these CYP2F enzymes. Both substrate binding to CYP2F2 and metabolic clearance by CYP2F enzymes correlate with the lipophilicity, parameter, log P (where P is the octanol/water partition coefficient of the substrate). Other features of CYP2F substrate binding are likely to include pi-pi stacking interactions between aromatic rings and hydrogen bonding in some cases. The metabolism of the respiratory toxicant naphthalene is compared and contrasted between three mammalian species, namely mouse, rat and human. The CYPs involved in the metabolic activation and detoxification of naphthalene are discussed in the light of current evidence from both experimental and theoretical studies. It is noted that the CYP2F subfamily enzymes are associated with the activation of naphthalene in all three mammalian species, although there are marked differences between man and the two rodent species in the toxicity of this compound.
Lewis
David F V
DF
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK. d.lewis@surrey.ac.uk
Ito
Yuko
Y
Lake
Brian G
BG
D000595:Amino Acid Sequence; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D013045:Species Specificity
D009281:Naphthalenes; C031721:naphthalene; D003577:Cytochrome P-450 Enzyme System; C497724:CYP2F4, rat; C110333:Cyp2f2 protein, mouse; C110332:CYP2F1 protein, human; D000072467:Cytochrome P450 Family 2; C110331:cytochrome P-450 CYP2F3 (goat)