Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver

Abstract

Various mutationally impaired genes are often found in malignant tumors of animals and humans. At the same time, a large number of carcinogens demonstrate positive activity in different in vitro tests for mutagenicity. These findings are indicative of a geno- toxic mechanism of carcinogen action. It is considered that chemically active carcinogens induce mutations (and tumors) directly interacting with DNA, while inactive substances are mutagenically activated in the processes of cellular metabolism in target tissues. The aminoazo dyes was found to be activated by N-hydroxilation and subsequent conjugation with sulfuric acid catalyzed by the enzyme sulfotransferase. Previously we found that it is activated metabolites of ortho-aminoazotoluene that are responsible for its inhibitory effect on hormonal induction of tyrosinaminotransferase activity in the liver of sensitive mice. Inhibition of sulfoconjugation of 4-aminoazobenzene, another hepatocarcinogen for mice, by pentaclorophenol was reported to reduce its both mutagenic and carcinogenic activity. In this paper, we confirmed this observation. But we found that, when used ortho-aminoazotoluene, pentaclorophenol inhibited its mutagenic activity, but significantly stimulated the hepatocarcinogenic potency. It seems that carcinogenic action is provoked by unmetabolysed ortho-aminoazotoluene per se or some of its nonsulfated derivatives. The results of our comparative study with ortho-aminoazotoluene and 3.4-benzopyrene are in contradiction with the genotoxic theory of carcinogenesis: both are similarly activated by mouse liver enzymes, but induce tumors in different tissues: the former, hepatocellular carcinomas and the latter, splenic lymphoma. The conclusion was made that the accepted notion about the mechanism of carcinogenesis has to be revised.

Keywords

• ortho-aminoazotoluene
• sulfoconjugation
• mutagenic activation
• carcinogenicity