IN 1952 Bonser, Clayson, Jull and Pyrah examined the carcinogenic action of 2-naphthylamine (I) and the hydrochloride of one of its metabolites, namely, 2-amino-1-naphthol (II), by means of the implantation of paraffin wax pellets containing the chemicals into the lumen of the mouse bladder. On the basis of experiments on forty-two mice they concluded that whereas the parent amine, 2-naphthylamine, was not active under these conditions the metabolite, 2-amino-1-naphthol was carcinogenic.The carcinogenicity of 2-amino-l-naphthol and the absence of such activity with 2-naphthylamine led Clayson (1953) to suggest that aromatic amines and certain other compounds were carcinogenic because of their conversion in the animal body to ortho hydroxy-amines. As a first step in testing this hypothesis it was necessary to show that ortho hydroxy-amines are in fact carcinogenic.It has recently been shown that 4-aminodiphenyl (para-xenylamine, VII) elicits biological responses similar to 2-naphthylamine. It is an industrial bladder OH OSO3H
Adrenocortical cells obtained from adult rats were propagated in monolayer culture. Depending on culture conditions, they grew either as lipid-containing epithelial-like cells with a high level of steroid production, or as fibroblast-like cells with a low level of steroid production. The major fluorogenic steroid secreted by both morphologic forms of adrenal cortical cell was corticosterone as determined by chromatography and acid fluorometry. Basal fluorogenic steroid production per 10(6) cells over 24 h was: epithelial-like cells, 5.0-mug; fibroblast-like cells, 0-014 mug. Stimulation with ACTH for 5 days increased fluorogenic steroid production and induced morphologic changes in both adrenal cell forms. ACTH stimulation of fluorogenic steroid production by both cell forms reached a maximum after 3 days, then dropped to a refractory state after 5 days. With maximal ACTH stimulation, production increased 25-fold in fibroblast-like cells and five-fold in epithelial-like cells. The latter rate of corticosterone production is similar, per cell, to ACTH-stimulated adrenal glands in vivo. Progressive morphologic changes were observed with ACTH stimulation: epithelial-like cells retracted from the substratum and lost lipid inclusions; fibroblast-like cells became more epithelial-like. Both adrenal cell types formed intermediates from [4-(14)C] pregnenolone including pregn-5-ene-3 phi, 20 alpha-diol and 20 alpha-hydroxy-pregn-4-en-3-one. Control cultures of muscle fascia fibroblasts did not produce corticosterone or intermediates from [4-(14)C[ pregnenolone and did not respond to ACTH functionally or morphologically.
IN 1951, Bonser, Clayson and Jull published some of the results of a quantitative study of the metabolism of 2-naphthylamine by various species. An apparent correlation was demonstrated between the proportion of a dose of 2-naphthylamine (I) excreted by way of the urine as 2-amino-1-naphthol derivatives (II) and the biological response of the species to treatment with 2-naphthylamine.Thus it was shown that the dog, which is particularly susceptible to 2-naph-thylamine carcinogenesis, excretes 55 to 70 per cent of a dose of 2-naphthylamine as 2-amino-1-naphthol conjugates, whereas the mouse, rat and rabbit, which are less susceptible, excrete smaller quantities in this form. Quantitative studies also revealed that the concentration of 2-amino-l-naphthol derivatives in the urine relative to the plasma was approximately 200:1 and from this it was concluded that the exposure of the urinary tract epithelium to the metabolite was very much greater than that of any other part of the body.Evidence was also presented (Bonser et al., 1951) that synthetic 2-amino-1-naphthol hydrochloride (III) was a carcinogen, using the method devised by Jull (1951)
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