Dual ligand binding of pyridylalkanamides to microsomal cytochrome P-450.
Twelve homologous and regioisomeric pyridylalkanamides were examined spectrally for their binding affinity to cytochrome P-450 in phenobarbital- and 3-methylcholanthrene-induced rat liver microsomes. The pKs values were calculated by the Lineweaver-Burk method and by non-linear analysis using both a one ligand-one acceptor and a one ligand-two acceptor model. The latter model best fits most of the data, confirming that two pKs values exist for most derivatives in the 3-pyridyl and 4-pyridyl series. Structure-binding relationships are discussed. The two binding constants are hypothesized to arise from a dual mode of binding to the ferric ion. At low ligand concentrations, binding to hexacoordinated cytochrome P-450 occurs and involves displacement of an endogenous 6th ligand; at higher concentrations, the ligands bind to the pentacoordinated P-450, resulting in a high-to-low spin shift.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D008748:Methylcholanthrene / Q000494:pharmacology; D008797:Metyrapone / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D011725:Pyridines; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital; D008797:Metyrapone