The fate of 4-cyanoacetanilide in rats and mice; mechanism of formation of a novel electrophilic metabolite.
1. The metabolic fate of 4-cyanoacetanilide (CAA), labelled with 14C and 13C in the N-acetyl group, was studied in rats (oral dose, 22.5 mg/kg) and mice (oral dose 21.7 mg/kg). 2. The metabolic profile in the urine of rats was compared with that obtained previously with 4-cyano-N,N-dimethylaniline (CDA) and confirms the intermediacy of CAA in the metabolism of CDA. 3. The precursor of a major metabolite of CDA and CAA (the mercapturic acid N-acetyl-S-[2-keto-2-(4-cyanoanilino)ethyl]cysteine, metabolite C) was identified in the urine of CAA-dosed rats as the O-sulphate conjugate of N-(4-cyanophenyl)glycolamide. 4. Pretreatment of rats with the sulphotransferase inhibitor pentachlorophenol reduced the yield of the mercapturic acid metabolite C, further indicating the intermediacy of a sulphate conjugate. 5. Metabolite C was not formed from CAA by mice; thus, this species difference, also observed with CDA, occurs at the level side-chain (acetyl) hydroxylation as well as at N-acetylation of 4-cyanoaniline as previously proposed. 6. The significance of this pathway as a bioactivation reaction of CDA, CAA and other acetanilides is discussed.
Hesk
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Shell Research Ltd., Sittingbourne Research Centre, Kent, UK.
Hutson
D H
DH
Logan
C J
CJ
D000083:Acetanilides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000814:Aniline Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D010416:Pentachlorophenol / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013431:Sulfates / Q000378:metabolism
D000083:Acetanilides; D000814:Aniline Compounds; D013431:Sulfates; C050119:4-cyanoacetanilide; C042318:4-cyano-N,N-dimethylaniline; D010416:Pentachlorophenol