title: The formation and metabolism of N-hydroxymethyl compounds--IX. N-(acetoxymethyl)-4-chlorobenzamide: an electrophile but not a mutagen in Salmonella typhimurium.
abstract: The electrophilic properties of 4-chloro-N-(hydroxymethyl)benzamide as a model compound of carbinolamides formed during the metabolic oxidation of N-methylamides were investigated. 4-Chloro-N-(hydroxymethyl)benzamide did not react with nucleophiles such as cyanide or glutathione under physiological conditions. In contrast, N-(acetoxymethyl)-4-chlorobenzamide yielded the cyanomethylamide with KCN and S-(4-chlorobenzamidomethyl)glutathione with glutathione. Under nonaqueous conditions, N-(acetoxymethyl)-4-chlorobenzamide reacted avidly with ethanethiol, with methanol and with diethylamine in the presence of base, whereas 4-chloro-N-(hydroxymethyl)benzamide did not afford products under these conditions. These results show clearly that N-(acetoxymethyl)-4-chlorobenzamide is the precursor of reactive electrophilic methyleneimines. 4-Chloro-N-(hydroxymethyl)benzamide was not biotransformed to such electrophilic species when incubated with mouse hepatic microsomes or a microsomal supernatant with acetyl-CoA or a PAPS generating system. Neither 4-chloro-N-(hydroxymethyl)benzamide nor its acetate ester were mutagenic in the short term bacterial assay using Salmonella typhimurium. Nevertheless, esters of carbinolamides, such as N-(acetoxymethyl)-4-chlorobenzamide, might possess toxic or carcinogenic properties.
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects
chemical_list: D001549:Benzamides; D009153:Mutagens; C050283:N-(acetoxymethyl)-4-chlorobenzamide; C050284:4-chloro-N-(hydroxymethyl)benzamide