N-hydroxy-N-arylacetamides. II: Molecular aspects of ferrihaemoglobin formation by N-hydroxy-N-arylacetamides and arylhydroxylamines in the rat.

Abstract

Ferrihaemoglobin (HbFe3+) formation in rats after i.p. injection of 6 N-hydroxy-N-arylacetamides has shown that N-hydroxy-4-chloroacetanilide(N-hydroxy-4ClAA) was the most active and N-hydroxy-2-acetylaminofluorene(N-hydroxy-2AAF) the least active compound tested. As N-hydroxy-N-arylacetamides were thought to produce HbFe3+ only after enzymic N-deacetylation, the corresponding arylhydroxylamines were also tested for HbFe3+-forming activity and were found to be more active, N-hydroxy-4-chloroaniline(N-hydroxy-4ClA) being one of the most active and N-hydroxy-2-aminofluorene(N-hydroxy-2AF) the least active compound tested. N-Hydroxy-4-chloroacetanilide given i.p. to rats more rapidly invaded the blood and produced larger amounts of ferrihaemoglobin than did N-hydroxy-2-acetylaminofluorene, due to differences in their availability in plasma. Injection of 50 mg/kg of N-hydroxy-4-chloroacetanilide gave similar concn of HbFe3+ and 4-chloronitrosobenzene(4-CINOB) as injections of 8 mg/kg of N-hydroxy-4-chloroaniline, indicating that the arylhydroxylamine, after N-deacetylation, was the active molecule in vivo. The concn of 4-chloronitrosobenzene declined faster than HbFe3+ concn. 4-Chloronitrosobenzene therefore is a further example of a 'hit-and-run' chemical. Inhibition by the microsomal carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate(BNPP), indicated that ferrihaemoglobin formation by 4-chloroacetanilide, but not by N-hydroxy-4-chloroacetanilide, depends on the enzymic activity of hepatic microsomal carboxylesterases.