Mutagenicity of the O-esters of N-acylhydroxylamines for Salmonella

Abstract

Several hydroxamic acids, RCONHON, have been shown to be directacting mutagens for Salmonella. Hydroxamic acids may be metabolically converted to O-sulfonate and O-acetate derivatives by mammals. Thus, the O-sulfonate, O-formate, O-acetate and O-propionate esters of 2-naphthohydroxamic acid and 4- n-butoxyphenylacetohydroxamic acid were synthesized as model compounds and examined in Salmonella typhimurium TA98 for mutagenicity in order to elucidate the activation mechanisms of hydroxamic acids. In addition, the mutagenicity of N-methyl-2-naphthohydroxamic acid and of 2-naphthylisocyanate, a rearrangement product of the O-sulfonate, were also tested. Among these chemicals tested, only 2-naphthohydroxamic acid and its O-formate, O-acetate and O-propionate were mutagenic. The O-acetate and O-propionate were more mutagenic than the O-formate, which was as mutagenic as 2-naphthohydroxamic acid. Addition of rat liver cytosol or microsomes greatly decreased the mutagenicity of the O-acetate and O-propionate, but not that of the O-formate or 2-naphthohydroxamic acid. An examination of the chemical stability of these compounds showed that the O-sulfonate ester of 2-naphthohydroxamic acid underwent the Lossen rearrangement in a neutral solution to form 2-naphthylisocyanate, which subsequently formed 2-aminonaphthalene and N,N′-di-2-naphthylurea. The O-formate simply underwent hydrolysis to form 2-naphthohydroxamic acid. Neither the O-acetate nor the O-propionate was readily hydrolyzed in neutral solution, but both of them were hydrolyzed to form 2-naphthohydroxamic acid in the presence of rat liver cytosol and microsomes. Rat liver cytosol also catalyzed the transfer of the acyl group from the O-acetate, but not from the O-propionate, derivative of 2-naphthohydroxamic acid to 4-aminoazobenzene. These results suggest that the NH group of 2-naphthohydroxamic acid is essential to the mutagenicity and the O-esterification may be an activation pathway for the mutagenicity of hydroxamic acids. Thus, the activation of hydroxamic acids may not be similar to that of N-arylhydroxamic acids whose mutagenicity in Salmonella has been known to be enhanced by rat liver cytosolic and microsomal enzymes.