Relationship between molecular structure and cytochrome P450-metabolic intermediate complex formation, studied with orphenadrine analogues.
Complexation of ferrous cytochrome P450 by metabolic intermediates formed during NADPH-catalyzed metabolism of compounds structurally related to orphenadrine was studied. This so-called metabolic intermediate complexation was determined in rat liver microsomes, obtained from phenobarbital-pretreated rats, at 455 nm using 33 microM of the orphenadrine derivatives. Using secondary amine derivatives with various N-alkyl substituents, a parabolic relationship between the logarithm of percentage of cytochrome P450 complexation and hydrophobic fragmental constant was observed. The derivative with a bulky tertiary butyl group, however, was devoid of metabolic intermediate-complexing activity. This indicates that steric factors besides lipid solubility may govern the complexing activity; also substitution at the phenyl group affects metabolic intermediate complex formation.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009966:Orphenadrine / Q000031:analogs & derivatives* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D009966:Orphenadrine; D010634:Phenobarbital