The metabolism of N,N-dimethylaniline by isolated rat hepatocytes: identification of a novel N-conjugate.
1. Incubation of N,N-dimethylaniline (DMA) with isolated rat hepatocytes resulted in the production of N-methylaniline, aniline, N,N-dimethylaniline N-oxide (DMA N-Oxide) and a highly water-soluble metabolic tentatively identified as N-methylaniline N-glucuronide. 2. After the removal of aniline, N-methylaniline and DMA, treatment of the media with either strong acid or beta-glucuronidase, resulted in the release of N-methylaniline, identified by chromatography and mass spectrometry. 3. Pre-incubation of rat hepatocytes with 2 mM D-galactosamine, which decreased 7-hydroxycoumarin conjugate formation by 40%, selectively decreased the formation of this highly water-soluble metabolite from DMA by 70%. DMA N-demethylase and N-oxidase activities remained unchanged. 4. Incubation of rat hepatocytes with N-methylaniline resulted in the production of the novel metabolite, the formation of which was proportional to cell number, incubation time, and N-methylaniline (substrate) concentration. 5. The N-glucuronidation of the secondary N-alkylarylamine, N-methylaniline, by rat hepatocytes represents a quantitatively important and previously uncharacterized route of metabolism in these cells. Further studies are, however, required to identify this metabolite unequivocally as the N-glucuronide of N-methylaniline.
Sherratt
A J
AJ
Department of Pharmacy, University of Manchester, UK.
Damani
L A
LA
D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014468:Umbelliferones / Q000378:metabolism
D000814:Aniline Compounds; D005965:Glucuronates; D014468:Umbelliferones; C060261:N-methylaniline N-glucuronide; C031477:7-hydroxycoumarin; C015157:N,N-dimethylaniline; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C021313:methylaniline