Comparison of the mixed function oxidase-catalyzed metabolism of a series of dialkyl p-nitrophenyl phosphorothionates

Abstract

Various concentrations of dimethyl, diethyl, di- n-propyl and di- n-butyl p-nitrophenyl phosphorothionate were incubated with rabbit liver microsomes, and the rates of formation of the corresponding dimethyl, diethyl, di n-propyl and di n-butyl p-nitrophenyl phosphates and dimethyl, diethyl, di n-propyl and di n-butylphosphorothioic acids were determined. From these data the apparent K m and V max for the formation of each metabolite was calculated. The maximum rate of metabolism ( V max) was found to vary with the size of the alkyl group. The maximal rate of metabolism of the dialkyl p-nitrophenyl phosphorothionates to the dialkyl p-nitrophenyl phosphates was exhibited by the di n-propyl and di n-butyl compounds. The maximal rate of metabolism to the dialkylphosphorothioic acids was shown by the dimethyl compound. A linear free energy plot failed to show a significant correlation between the polar effect of the alkyl groups (as quantitated by the Taft σ ∗ constant) or the alkoxy groups (as quantitated by the Kabachnik σφ constant), and the maximal rates of metabolism of these compounds to either the dialkyl p-nitrophenyl phosphates or the dialkylphosphorothioic acids. Although the inductive and steric properties of the alkyl groups are undoubtedly important, there must be additional factors responsible for the differences seen in the rates of metabolism of this series of compounds.