The formation and metabolism of N-hydroxymethyl compounds--III. The metabolic conversion of N-methyl and N,N,-dimethylbenzamides to N-hydroxymethyl compounds.

D Ross, P B Farmer, A Gescher, J A Hickman, M D Threadgill

Index: Biochem. Pharmacol. 32(11) , 1773-81, (1983)

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Abstract

The stability of metabolically-generated N-(hydroxymethyl) compounds was investigated using a series of N-methylbenzamides as model substrates. N-(Hydroxymethyl)-benzamide was characterized as a major metabolite of N-methylbenzamide in vitro, and was also identified as a urinary metabolite of N-methylbenzamide. N-(Hydroxymethyl) compounds were also found as metabolites of 4-chloro-N-methylbenzamide and 4-t-butyl-N-methylbenzamide in vitro. Thus substitution in the 4-position of the phenyl ring of derivatives of N-(hydroxymethyl)-benzamide did not affect their stability sufficiently to cause degradation to formaldehyde under the conditions used. N-(Hydroxymethyl)-N-methylbenzamide was identified as a metabolite of N,N-dimethylbenzamide in vitro. However, N-(hydroxymethyl)-N-methylbenzamide was less stable than N-(hydroxymethyl)-benzamide under alkaline conditions. Furthermore, N-(hydroxymethyl)-N-methylbenzamide, unlike N-(hydroxymethyl)-benzamide and its 4-substituted derivatives, was positive in the colorimetric assay for formaldehyde, presumably because of its degradation to produce formaldehyde. Thus substitution on the nitrogen atom which bears the methyl group in N-methylbenzamide markedly affected the stability of the N-methylol produced during oxidative metabolism. N-Formylbenzamide was identified as a metabolite of N-methylbenzamide in suspensions of mouse hepatocytes and also in vivo. The mechanism for its production probably involves the generation of N-(hydroxymethyl)-benzamide.