Mutagenic Activation Reduces Carcinogenic Activity of Ortho-Aminoazotoluene for Mouse Liver

Abstract

Pentachlorophenol (aromatic amine and azo stain metabolic stimulation inhibitor) reduced the hepatocarcinogenic activity of 4-aminoazobenzene and reduced that of ortho-aminoazotoluene in suckling mice. Both 4-aminoazobenzene and ortho-aminoazotoluene exhibited mutagenic activity in Ames' test in vitro on S. typhimurium TA 98 strain with activation with liver enzymes; this mutagenic activity was similarly suppressed by adding pentachlorophenol into activation medium. Induction of xenobiotic metabolism enzymes, stimulating the mutagenic activity of ortho-aminoazotoluene, suppressed its carcinogenic effect on mouse liver. Hence, ortho-aminotoluene (the initial compound), but not its mutagenic metabolites, was the direct active hepatocarcinogen for mice.

Suppression of Sulfoconjugation Reduces the Protective Effect of Ortho-Aminoazotoluene on Hepatocarcinogenesis Induced by Diethylnitrosamine in Mice

“…As PCP had no hepatocarcinogenic activity of its own [3] and did not modify the carcinogenic effect of DENA [6] (which did not need sulfoconjugation), its effect on OAT activity was presumably realized via sulfoconjugation. However, if ethyl ethers of aminoazobenzene and its N-methyl derivatives were more carcinogenic than the initial compounds [3,5], conjugation with sulfuric acid would attenuate the OAT carcinogenic activity, according to our data [2,3]. This indicated disagreement between metabolic stimulation and carcinogenic characteristics of these aminoazocompounds.…”

“…It was hypothesized not once that carcinogenesis developed from disorders in the genome function, but not structure, and the cell proteins (presumably transcription factors), involved in regulation of morphogenetically signifi cant genes expression, served as targets for the carcinogen activity [1][2][3]. A chemical reaction with these targets was not at all necessary for the carcinogen modulating them; noncovalent binding based on the steric affi nity could be quite suffi cient for this modulation.…”

“…However, the relationship between the protective effect of OAT and its own metabolism remained unclear -whether it was caused by the initial compound or some of its derivatives forming in the organism. We tried to answer this question in our experiments with pentachlorophenol (PCP) -specifi c inhibitor of hepatic sulfotransferase, conjugating the initially oxidized metabolites of aminoazostains with the formation of their highly reactive ethyl ethers [2,3].…”