The fate of 4-cyano-N,N-dimethylaniline in rats; a novel involvement of glutathione in the metabolism of anilines.

D H Hutson, S K Lakeman, C J Logan

Index: Xenobiotica 14(12) , 925-34, (1984)

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Abstract

4-Cyano-N,N-dimethylaniline (CDA), when administered to rats as a single oral dose (18.5 mg/kg), was rapidly absorbed and eliminated as a mixture of metabolites in the urine (86% dose after 24 h). Residues in tissues after 48 h, expressed as microgram equiv. of CDA, were: liver, 0.35; kidney, 0.28; testes, 0.08; fat, 0.06; bone marrow, 0.15 and blood, 0.32. Absorption, metabolism and elimination following four consecutive daily doses of CDA (65 mg/kg) were similar to those at the lower dose. The major metabolite was 2-amino-5-cyanophenyl sulphate with its mono- and di-N-methyl analogues as minor metabolites. 4-Cyanoaniline, its N-acetyl derivative and an unstable derivative were also found as metabolites. Three sulphur-containing metabolites with methylsulphinyl-, methylsulphonyl-, and N-acetylcysteinyl-groups attached to the C2 atom of an N-acetyl group were identified, the latter accounting for 10.3% and 4.1% of the low and high doses, respectively. The sulphur-containing metabolites indicate the involvement of glutathione in metabolism at the N-acetyl group. This implies the generation of an electrophilic intermediate, possibly the sulphate conjugate of an N-glycolylaniline, in the metabolism of CDA.