METABOLISM OF 4-NITROANILINE BY RAT-LIVER MICROSOMES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (2) , 179-185
Abstract
4-Nitroaniline is an industrial intermediate used in the synthesis of a variety of pharmaceutical, veterinary, agricultural and other consumer products. The principal rat liver microsomal metabolite of 4-nitroaniline was isolated by high pressure liquid chromatography [HPLC] and was characterized as 2-amino-5-nitrophenol (2-hydroxy-4-nitroaniline) by comparison of its mass, NMR and UV spectra and HPLC retention time to the synthetic compound. A metabolite with the chromatographic retention time of authentic N-hydroxy-4-nitroaniline was not detected. Pretreatment of rats with phenobarbital and 3-methylcholanthrene increased the rate of conversion of 4-nitroaniline to 2-hydroxy-4-nitroaniline by 2-fold and 4-fold, respectively; the reaction required NADPH and was inhibited by heat treatment of microsomes, by Ar and CO O2 atm and by the cytochrome P-450 inhibitor, 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine. In the presence of an (18O2) atmosphere, 18O was quantitatively incorporated into the metabolite. Microsomes did not catalyze the isomerization of N-hydroxy-4-nitroaniline to 2-hydroxy-4-nitroaniline. A primary isotope effect was not observed upon comparison of the rate of conversion of 2,6-dideutero-4-nitroaniline to 2-hydroxy-4-nitroaniline with that of the nondeuterated compound. The 2-hydroxy-4-nitroaniline derived from microsomal incubation mixtures of 2,6-dideutero-4-nitroaniline contained about 20%, 3,6-dideutero-2-hydroxy-4-nitroaniline.

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