Benz- and dibenzacridines represent an important class of environmental toxicants which present a potential health hazard both to the general public and to workers involved in coking and fossil fuel conversion operations. In spite of the potential carcinogenicity of these chemicals, there is extremely limited information available on their metabolism or mechanism of action. The proposed research is aimed at identifying reactive metabolites of dibenz(a,h)acridine [DB(a,h)AC] which may be involved in the mutagenesis/carcinogenesis of this chemical. A major objective of the proposed research is to investigate whether the """"""""bay-region"""""""" hypothesis proposed for the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs) can be extended to their aza analogs.
The specific aims of the proposed research are: (1) to synthesize several diol epoxides and dihydrodiol derivatives of DB(a,h)AC, (2) to assess the intrinsic mutagenic activity of DB(a,h)AC diol epoxided and the metabolic activation of DB(a,h)AC dihydrodiols in in vitro mutagenicity assays using Salmonella typhimurium, (3) to correlate the biological activity of diol epoxides with their chemical reactivity and predicted electronic properties in order to assess whether calculable electronic properties can be used to predict the biological activity of the diol epoxides of aza-PAHs, as demonstrated with certain PAHs, (4) to assess the role of aza substitution and the conjugative effect of nitrogens in the chemical reactivity and the mutagenicity/carcinogenicity of the bay-region diol epoxides, in an attempt to elucidate the molecular factors which influence the carcinogenic activity of dibenzacridines and other aza-PAHs, and (5) to determine the extent to which DB(a,h)AC is converted to its dihydrodiols by rat liver microsomes. The long-term aim of the research is to understand the mechanism(s) involved in the carcinogenesis of polynuclear aza-heteroaromatic hydrocarbons.
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| Kumar, S; Chang, R L; Wood, A W et al. (2001) Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin. Carcinogenesis 22:951-5 |
| Kumar, S; Singh, S K; Kole, P L et al. (1995) Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes. Carcinogenesis 16:525-30 |
| Wood, A W; Chang, R L; Katz, M et al. (1989) Mutagenicity of dihydrodiols and diol epoxides of dibenz[a, h]acridine in bacterial and mammalian cells. Cancer Res 49:6981-4 |
| Steward, A R; Kumar, S; Sikka, H C (1987) Metabolism of dibenz[a,h]acridine by rat liver microsomes. Carcinogenesis 8:1043-50 |
