ROLE OF ACETYLTRANSFERASES IN THE METABOLISM AND CARCINOGENICITY OF AROMATIC-AMINES

The genotoxicity of N-substituted aryl compounds is dependent on their conversion to reactive metabolites, frequently through the production of reactive N-acetoxyarylamines. This activation is accomplished by a cetyltransferases that are widely distributed. In the rat, the product ion of N-acetoxyarylamines has been most clearly related to the induct ion of tumors in the mammary gland, but this pathway also appears to b e an important factor in the production of tumors in the liver, Zymbal gland and gastrointestinal tract. Expression of rat acetyltransferase s responsible for acetylation of the nitrogen and the oxygen of arylam ine derivatives (i.e., acetyltransferases 1 and 2) in bacterial cells has now permitted experiments which demonstrate that these enzymes exh ibit good affinities for and N-acetylation of the endogenous arylalkyl amines derived from tryptophan, i.e., tryptamine, 5-hydroxytryptamine (serotonin) and 5-methoxytryptamine, the immediate metabolic precursor of melatonin. Evidence that these reactions are likely to reflect rea l biological potentials is bolstered by histological localization of a cetyltransferase mRNAs with synthetic antisense oligodeoxynucleotide p robes. The results of these studies in rat indicate that the expressio n of acetyltransferase in tissues of the central nervous, gastrointest inal, urinary and reproductive systems is highly regulated, as it is i n other organs commonly associated with aromatic amine carcinogenicity , Similar experimental approaches have been successful with human live r, mammary gland, kidney and bladder preparations. These observations give evidence that genotoxic N-acetoxyarylamines are produced by acety ltransferases that can metabolize, and possibly modulate, the hormonal and neurotransmitter effects of endogenous arylalkylamines. These rel ationships may help explain the occasional induction of tumors in orga ns not usually considered as targets of aromatic amines, as well as ra ise the possibility that the production of N-oxidized endogenous subst rates may represent a mechanism for tumor induction in the absence of exogenous carcinogens.