Chemical & Pharmaceutical Bulletin 1990-09-01

Regioselective N-acetylation as a route of nitro-9-phenylenediamine metabolism by rat liver cytosol.

M Nakao, Y Goto, Y Matsuki, A Hiratsuka, T Watabe

Index: Chem. Pharm. Bull. 38(9) , 2561-6, (1990)

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Abstract

Regioselectivity in N-acetylation of nitro-0-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 N4-position to afford the N4-monoacetate, a major urinary metabolite in the rat, when incubated with rat liver cytosol fortified with acetyl-coenzyme A. N1-Acetylation of nitro-p-phenylenediamine did not take place even when the N4-monoacetate was used as a substrate, suggesting a strong steric hindrance effect of the ortho nitro group on the enzymatic N1-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 N1- and N4-monoacetates of 1,2,4-triaminobenzene. The monoacetates yielded the N1,N4-diacetate, another major urinary metabolite of the hair dye component, in the rat, without concomitant formation of the N2,N4-diacetate or the N1,N2,N4-triacetate. The triacetate was formed only from the N1,N2-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.(ABSTRACT TRUNCATED AT 250 WORDS)