Regioselective N-Acetylation as a Route of Nitro-p-phenylenediamine Metabolism by Rat Liver Cytosol

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Regioselectivity in N-acetylation of nitro-p-phenylenediamine, a widely used hair dye component, by rat liver cytosolic N-acetyltransferases was studied in relation to its substituent effects on enzymatic N-acetylation of mono-substituted anilines. Nitro-p-phenylenediamine was acetylated specifically at the N^4-position to afford the N^4-monoacetate, a major urinary metabolite in the rat, when incubated with rat liver cytosol fortified with acetyl-coenzyme A. N^1-Acetylation of nitro-p-phenylenediamine did not take place even when the N^4-monoacetate was used as a substrate, suggesting a strong steric hindrance effect of the ortho nitro group on the enzymatic N^1-acetylation. The steric hindrance effect of the nitro group on the cytosolic N-acetylation of the ortho amino group was revealed by a comparative study carried out by using aniline, three respective regioisomers of nitroanilines and phenylenediamines as model substrates. The comparative study also indicated the enzymatic N-acetylation of the mono-substituted anilines to be strongly influenced by the electronic effect of the substituents.Regioselective N-acetylation in the hepatic cytosol was also investigated with N^1- and N^4-monoacetates of 1,2,4-triaminobenzene. The monoacetates yielded the N^1,N^4-diacetate, another major urinary metabolite of the hair dye component, in the rat, without concomitant formation of the N^2,N^4-diacetate or the N^1,N^2,N^4-triacetate. The triacetate was formed only from the N^1,N^2-diacetate in the enzymatic reactions. A comparative study, carried out by using N-mono-acetates of three regioisomeric phenylenediamines, indicated that the N-acetyl group had a potent steric hindrance effect on the primary amino group at the ortho position.Thus, the present in vitro study strongly suggested that the two major urinary metabolites, nitro-p-phenylenediamine N^4-acetate and 1,2,4-triaminobenzene N^1,N^4-diacetate, of the hair dye component could be formed, at least in the rat liver, by the enzymatic N-acetylation of the corresponding amines.
社団法人日本薬学会の論文
1990-09-25

Regioselective N-Acetylation as a Route of Nitro-p-phenylenediamine Metabolism by Rat Liver Cytosol

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