2-Acetylaminofluorene mechanism

Work with the carcinogen acetylaminofluorene found that residues of the compound in ribosomal RNA may correlate more closely with liver tumor formation than residues in DNA. Direct interactions with the mechanisms of protein synthesis, or with DNA and RNA polymerase enzymes, can also be seen as possible mechanisms. For instance, a modification of the polymerase enzymes by a carcinogen, either directly or indirectly, could lead to the erroneous replication of DNA or RNA and hence the permanent incorporation of a mutation. 

Clearly, the mechanism(s) underlying the carcinogenesis of acetylaminofluorene is very complex, and sometimes apparently conflicting and confusing data may reflect the fact that several different metabolic pathways are involved, which are more or less predominant in different tissues and in different animal species. It has been suggested, for instance, that the sulfate ester of N-hydroxyacetylaminofluorene is responsible for cytotoxicity and cell death, cell proliferation, and therefore promotion, whereas an N-hydroxyaminofluorene metabolite is responsible for initiation. Thus, both pathways would be necessary (Fig. 7.1). 

Banner et al., (21) found that selenium did not influence the acute alterations induced by 2-acetylaminofluorene or methylazoxymethanol and suggested that the anticarcinogenic properties of selenium were due to a mechanism other than an interference with carcinogen activation and interaction with cellular macromolecules. 

Waldmann, P., Pivcevic, B., Muller, W.E., Zahn, R.K. and Kurelec, B. (1995) Increased genotoxicity of 2-acetylaminofluorene by modulators of multixenobiotic resistance mechanism studies with the freshwater clam Corbicula fluminea. Mulat. Res., 342, 113-123. 

J., Richardson, C.C., Romano, L.J., and Ellenberger, T. (2004) Crystal structures of 2-acetylaminofluorene and 2-aminofluorene in complex with T7 DNA polymerase reveal mechanisms of mutagenesis. Proc. Natl. Acad. Sci. USA, 101, 16186-16191. 

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