2-acetylaminofluorene (AAF) is one of the most extensively used model compounds in studies of the metabolism and mechanism of action of carcinogenic aromatic amides and amines. Although AAF is known to induce liver tumors in several mammalian species, rainbow trout is remarkably resistant to the hepatocarcinogenic effect of this chemical even though the rainbow trout liver has the capacity to activate AAF to mutagenic metabolites. The applicant is interested in examining the mechanism(s) underlying the resistance of rainbow trout to AAF-induced hepatocarcinogenesis. A number of factors, (e.g., pharmacokinetics, metabolism, interaction with DNA, DNA repair, rate of cell division, immune competence, tumor promotion, etc.) may interact to determine species susceptibility/resistance to a chemical carcinogen. In the proposed project, the applicant plans to assess the role of certain key factors in determining the resistance of rainbow trout liver to the carcinogenic action of AAF. These factors include disposition of AAF, its biotransformation (both activation and detoxification), interaction of reactive AAF metabolites with DNA, and the repair of damaged DNA.
The specific aims of the proposed research are: (1) to investigate the in vitro metabolism of AAF and N-hydroxy-AAF by Shasta rainbow trout liver microsomes with regard to the rates of metabolism and metabolite profile, (2) to examine the metabolism of AAF in rainbow trout hepatocytes with special reference to the relative extent of competing activation and detoxification reactions which the chemical may undergo, (3) to examine the disposition of AAF in rainbow trout in vivo, with particular emphasis on the levels of AAF and its metabolites in the liver, (4) to assess the formation and persistence of AAF-DNA adducts in rainbow trout liver in vivo, and (5) to compare the data on the metabolism of AAF and the formation and persistence of DNA adducts in rainbow trout liver with the corresponding data published on the rat liver. The overall objective of the proposed research is to investigate the pathways which may be involved in the metabolism of carcinogenic aromatic amides and amines in rainbow trout (and possibly other fish species), and to elucidate the biochemical mechanism(s) underlying the resistance of rainbow trout to AAF-induced hepatocarcinogenesis.
| Steward, A R; Elmarakby, S A; Stuart, K G et al. (1995) Metabolism of 2-acetylaminofluorene by hepatocytes isolated from rainbow trout. Toxicol Appl Pharmacol 130:188-96 |
