Studies in Carcinogenesis with Azo Compounds I. The Action of Four Azo Dyes in Mixed and Pure Strain Mice*

It has been known since 1932 (23) that 4'-amino2,3'-azotoluene will induce liver tumors in rats receiving the dye orally. Later, Kinosita (10) demonstrated the superior carcinogenic activity of an isomeric azo dye, N,N-dimethyl-p-arninoazobenzene, toward the rat liver; this superiority was revealed both in the shorter minimal feeding period and in the shorter latent period. Both these azo dyes are methyl derivatives of the base, p-aminoazobenzene, which was long regarded as noncarcinogenic (8, 10, 14, 21, 23, 25). Consideration of the fact that 4'-amino-2,Y-azotoluene was carcinogenic although the amino group was not substituted, and also of the inhibitory action of pphenylenediamine, one of the products of reductive fission of p-aminoazobenzene, upon certain enzyme systems (8, 9, 20) led the present author to feed p-aminoazobenzene in a modified diet to rats for a long period. Unequivocal liver-cell carcinomas were found after 17 months' feeding, with metastases in one animal (11). Thus it appears that p-aminoazobenzene, as well as its 2,Y-dimethyl and N,N-dimethyl derivatives, is carcinogenic for the "liver of rats; methylation does not confer, but does greatly enhance, carcinogenic power, provided the methyl groups enter certain positions. Yoshida (25), and Sasaki and Yoshida (21) report having fed 2'-amino-4,5'-azotoluene for periods up to 476 days to rats without eliciting any liver tumors. Although Sasaki and Yoshida provide a structural formula for their compound that would show it to be 5'-amino-2,2'-azotoluene, and Cook and Kennaway (5) depict it as 4'-amino-2,2'-azotoluene, Miura (16), summarizing the experiments of Sasaki and Yoshida,