Possible Relation between Carcinogenicity and Ease of Hydrolysis in vitro of Derivatives of 2-Aminofluorene

Abstract

THE carcinogenicity of 2-acetylaminofluorene (I) administered orally to rats, was first reported in 1941 by Wilson, DeEds and Cox¹. Subsequent studies showed that the free amine (II) was substantially as carcinogenic in this species as the acetyl derivative². The values for LD ₅₀ on the basis of millimoles per kgm. also were found to be essentially the same³. It was then postulated that the free amine may be the essential carcinogen and that deacetylation is a necessary prelude to carcinogenesis⁴. Studies in vivo with 2-acetylaminofluorene labelled with carbon-14 in the ω-position⁵ revealed that deacetylation did indeed occur^6,7. In subsequent experiments in vitro the ability of rat liver slices and homogenates to deacetylate 2-acetylaminofluorene was demonstrated^8,9. Thus, N-derivatives of 2-aminofluorene that are difficult to hydrolyse to the free amine should be less carcinogenic than those that are easily hydrolysed. It is true, of course, that if a substituent renders the compound non-absorbable from the gut it would not be carcinogenic, even though it was hydrolysed readily both in vivo by liver enzymes, and in vitro by acids. On the other hand, derivatives that are converted to 2-aminofluorene by reactions other than hydrolysis would be carcinogenic.