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Relationship between molecular structure and cytochrome P450-metabolic intermediate complex formation, studied with orphenadrine analogues.

A Bast·E M Savenije-Chapel·J Noordhoek
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Abstract

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.

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AnimalsCytochrome P-450 Enzyme SystemIn Vitro TechniquesKineticsMicrosomes, LiverOrphenadrinePhenobarbitalProteinsRatsRats, Inbred StrainsJournal Article

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A Bast, E M Savenije-Chapel, J Noordhoek. 1984. Relationship between molecular structure and cytochrome P450-metabolic intermediate complex formation, studied with orphenadrine analogues.. https://doi.org/10.1002/jps.2600730723

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