Role of genotoxic and nongenotoxic effects in multistage carcinogenicity of aromatic amines.

Abstract

It has been demonstrated in several model systems that tumors arise in a multistage process. Carcinogenic aromatic amines are complete carcinogens, which usually produce tumors in typical target tissues without any additional treatment. The tissue specificity, however, cannot readily be explained by genotoxic effects, and the role of secondary effects is not well understood. Promotional pressure on initiated cells can be produced by endogenous factors but also by the chemical itself. Comparison of the effects on rat liver of 2-acetylaminofluorene (AAF) and trans4-acetylaminostilbene (AAS) provides some evidence that initiating and promoting properties of these chemicals can be separated. AAS is a strong initiator in rat liver but seems to lack promoting activity; AAF is a less efficient initiator but has tumor promoting properties. The results obtained so far indicate that promoting pressure is not produced by the acute, cytotoxic effects of AAF. It is therefore concluded that nongenotoxic, possibly receptor-mediated effects are involved.

The role of nongenotoxic mechanisms in arylamine carcinogenesis.

“…The purpose of this experiment was to obtain tumor material in order to study protooncogene mutation or activation, and to compare the lesions between the treatment groups in order possibly to demonstrate a specific lesion produced by 2 (Figure 1). This is underlined by the observation that body weight increase returns to normal when the chemical is removed from the feed.…”

“…The amines are 2-acetylaminofluorene (2-AAF), 2-acetylaminophenanthrene (AAP) and trans-4-acetylaminostilbene (AAS). The end points in rat liver are a) tumor formation, b) tumor initiation, c) acute toxicity, d) chronic toxi- city, and e) the generation of oxidative stress in mitochondria (1)(2)(3). It is well known that feeding of 2-AAF produces liver tumors in the rat (4).…”

“…Although they are complete carcinogens considering the whole animal, rat liver is not a target tissue. Since it was shown that in the liver both AAP and AAS yield reactive metabolites that bind to DNA, that the adducts are promutagenic lesions, and that liver tumors can be produced if an initiating treatment with these amines is followed by a promoting treatment in an initiation-promotion experiment, AAP and AAS may be called incomplete carcinogens and initiators for this tissue (2,8).…”