The formation and metabolism of N-hydroxymethyl compounds—I : The oxidative N-demethylation of N-dimethyl derivatives of arylamines, aryltriazenes, arylformamidines and arylureas including the herbicide monuron

Abstract

The metabolism of the N-methyl moieties of aryldimethylamines and N-methyl compounds of the general formula Aryl- X-N(Me) 2, where X is either —N=N— (3-aryl-1,1-dimethyltriazenes), —NHCO— ( N′-aryl- N, N-dimethylureas) or —N=CH— ( N′-aryl- N, N-dimethylformamidines) was studied using mouse liver microsomes. Products of microsomal metabolism were reincubated with mouse liver homogenate devoid of microsomes and assayed colourimetrically for formaldehyde. This allows metabolically generated formaldehyde to be distinguished from formaldehyde precursors. Whereas the N-methyl moieties of the aryldimethyltriazenes, formamidines and amines were metabolised to formaldehyde, the aryldimethylureas formed stable formaldehyde precursors upon metabolism. The products of metabolism of one such aryldimethylurea, the herbicide monuron ( N′-(4-chlorophenyl)- N, N-dimethylurea) were investigated using a high pressure liquid chromatographic method. Two metabolites were found on incubation of monuron with microsomes, one of which was identified as the N-desmethyl compound by mass spectrometry. The other product showed chromatographic properties similar to 4-chlorophenylurea but resembled the monomethylaryl urea on mass spectral analysis. It is concluded that this metabolite is likely to be N′-(4-chlorophenyl)- N-hydroxymethyl- N-methylurea. A urinary product of conjugative metabolism obtained after the administration of monuron to mice also gave the mass spectrum of the monomethyl compound after deconjugation which suggests that a conjugated N-hydroxymethyl compound may have been formed in vivo.