Role of N-acetyltransferase (NAT) polymorphism on 4,4'-methylene bis (2-chloroaniline) and 4,4'-methylenedianiline (MDA) acetylation, MDA hepatotoxicity and a proposal to study NAT expression in breast cancer

This thesis describes experiments to investigate the role of N-acetyltransferase polymorphism in 4, 4'-metheylenedianiline (MDA) hepatotoxicity in a rapid and slow acetylator rat model, the capability of recombinant human N-acetyltransferase isozymes to catalyze the N-acetylation of 4, 4'-methylene bis (2-chloroaniline) (MOCA) and 4, 4'-methylenedianiline (MDA), two aromatic diamine compounds that are suspected carcinogens in humans, and a dissertation proposal to study N-acetyltransferase gene expression in human breast cancer.; In the first chapter, a rapid and slow acetylator rat model is used to characterize the role of N-acetyltransferase polymorphism in MDA hepatotoxicity. Rapid acetylator (F344) and slow acetylator (WKY) rats administrated MDA showed more acute hepatotoxicity in the rapid acetylator rats compared with the slow acetylator rats. The role of the Nat2 polymorphism in MDA N-acetylation was also shown in liver cytosol and by recombinant expression of rat Nat isozymes. In the second chapter, investigations with recombinant human NAT2 allozymes showed that MOCA and MDA NAT activities catalyzed by the NAT2 5, NAT2 6, NAT2 7 and NAT2 14 clusters were reduced in comparison to NAT2 4, NAT2 11, NAT2 12 and NAT2 13 clusters. These results support a role for NAT polymorphism in their metabolism and carcinogenicity in humans. In the third chapter, preliminary results on three fresh breast tumor and normal adjacent tissues showed NAT 1 up-regulation in breast tumor in comparison to adjacent normal tissues. Experiments to further investigate this finding as a dissertation project are proposed.