Carcinogenicity of 2-Naphthylhydroxylamine and 2-Naphthylamine

Abstract

THE discovery of the N-hydroxylation of 2-acetamidofluorene in vivo (Cramer, Miller and Miller, 1959) had been followed by recognition that 4-acetamidobiphenyl (Miller, Wyatt, Miller and Hartman, 1961b) and 2-naphthylamine (Boyland, Manson and Nery, 1960;Troll and Nelson, 1961) are metabolised by similar routes. The carcinogenic aromatic amines are also metabolised to ortho aminophenols, some of which have been shown to be carcinogenic by the technique of bladder pellet implantation in mice (Bonser, Bradshaw, Clayson and Jull, 1956;Allen, Boyland, Dukes, Horning and Watson, 1957), but 2-naphthylhydroxvlamine, the N-hydroxy derivative of 2-naphthylamine, has induced a higher incidence of bladder tumours than any other compound tested (Bonser, Boyland, Busby, Clayson, Grover and Jull, 1963). The N-hydroxy derivatives of 2-acetamidofluorene and 4-acetamidobiphenyl appear to be proximate carcinogens when given intraperitoneally to rats (Miller, Miller and Hartman, 1961a;Miller, Wyatt, Miller and Hartman, 1961b).The present paper describes the potent carcinogenicity of the 2-naphthylhydroxylamine in comparison with that of the parent amine following multiple intraperitoneal injections in rats. A preliminary report of this work has already appeared (Boyland, Dukes and Grover, 1961). (Boyland, Manson and Nery, 1962). The hydroxylamine, which crystallized as cream-coloured plates (m.p. 137°) was stored in the dark at 40 until required for injection. 2-Naphthylamine and an unidentified red-coloured oxidation product were shown to be present as impurities by descending paper chromatography (Whatman No. 1) in light petroleum (b.p. 60-80°); acetone 4: 1. This fast-running solvent system has the advantage that paper chromatograms can be completed without decomposition of the hydroxylamine, and it has been found useful as a solvent for the thin-layer chromatography of naphthylamine derivatives on silica gel (Manson, unpublished work). Attempted purification of 2-naphthylhydroxylamine by recrystallization from chloroform (Baudisch and Fiirst, 1917) yielded a less pure product of lower melting point.Two groups each of 16 male Chester Beatty random inbred strain albino rats (200 g.) were used. Group A received intraperitoneal injections of 2-naphthyl-4

Further tests for carcinogenesis using newborn mice: 2-naphthylamine, 2-naphthylhydroxylamine, 2-acetylaminofluorene and ethyl methane sulphonate.

“…None were found in a group of 74 mice implanted with 2-naphthylamine/stearic acid pellets. Intraperitoneal injections of 2-naphthylhydroxylamine induced abdominal tumours in nine out of fifteen rats, while only two of fourteen rats developed sarcomas following similar treatment with 2-naphthylamine (Boyland, Dukes and Grover, 1963).…”

“…Clayson (1953) suggested that the aromatic amines were carcinogenic because of their conversion to ortho-hydroxylamines. Some of these compounds were shown to be carcinogenic by the technique of bladder pellet implantation in mice (Bonser, Bradshaw, Clayson and Jull, 1956), but 2-naphthylhydroxylamine, a metabolite formed by N-hydroxylation (Boyland, Manson and Nery, 1960), has induced a higher incidence of bladder tumours than any other compound tested (Bonser et al, 1963). More than half of 66 mice implanted with pellets of 2-naphthylhydroxylamine mixed with stearic acid developed bladder tumours.…”

Metabolism of 2-acetamidofluorene in the steppe lemming

“…The steppe lemming (Lagarus lagarus, Pall) has been recently introduced into cancer research (Pogosianz, Bolonina and Olshevskaja, 1960).This species was found useful in studies of skin cancer induction with certain polynuclear aromatic hydrocarbons and for transplantation experiments.Recent developments with carcinogenic aromatic amine derivatives have suggested that this class of compounds requires metabolic activation by hydroxylation on the nitrogen (Boyland, Dukes and Grover, 1963;Cramer, Miller and Miller, 1960; Heringlake, Kiese, Renner and Wenz, 1960;Irving, 1964;Miller, Cramer and Miller, 1960; Uehleke, 1964). In order to investigate their potential susceptibility to such chemicals, we determined whether steppe lemmings metabolized 2-acetamidofluorene (AAF) by N-hydroxylation, a reaction performed by a sensitive but not by a resistant species Weisburger et al, 1964a).…”

Tests for Carcinogenesis Using Newborn Mice: 1,2-Benzanthracene 2-Naphthylamine, 2-Naphthylhydroxylamine and Ethyl Methane Sulphonate

“…in oil) twice weekly for three months (Boyland, Dukes and Grover, 1961). Thirteen bladder carcinomas were found among 62 surviving mice following bladder implantation of crushed paraffin wax pellets containing 2-naphthylhydroxylamine (Bonser et al, 1963).…”