Metabolic activation routes of arylamines and their genotoxic effects.

Abstract

Two different types of DNA adducts are formed from many aromatic amines by bioactivation: N-acetylated and nonacetylated, arylamine DNA adducts. It has become clear from experiments using N-acetyl-2-aminofluorene and 2-aminofluorene adducts to C8 of deoxyguanosine that these two types of adducts may have different effects on DNA structure and DNA replication. We have determined blocking of DNA replication by various other N-acetylarylamine and arylamine deoxyguanosine adducts. It was found that the N-acetyl group in general is required for blocking of DNA replication; the nature of the aromatic moiety seems to be of minor importance. Little information is available on the genotoxic effects of these adducts in mammalian cells in vivo. We have tried to get more insight in this by investigating the clastogenicity, the initiation of preneoplastic cells, and the promotional effects of various aromatic amines from which different ratios of N-acetylarylamine DNA adducts to arylamine DNA adducts are formed in the rat liver. Our results show that formation of N-acetylarylamine adducts to C8 of deoxyguanosine in the liver is correlated with clastogenicity and hepatic promoting effect. Initiation capacities, however, seem to be correlated with formation of nonacetylated, arylamine adducts. Mechanisms by which formation of N-acetylarylamine DNA adducts may generate a promoting effect in the liver are discussed.