An investigation of the metabolism of N-nitroso-N-methylaniline by phenobarbital- and pyrazole-induced Sprague-Dawley rat liver and esophagus derived S-9 |
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| Authors: | B Gold J Farber E Rogan |
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| Affiliation: | 1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States;2. Immuneering Corporation, Cambridge, MA, United States;3. Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States;1. Safety Pharmacology, Bayer AG, Aprather Weg 18a, 42096 Wuppertal, Germany;2. UCB Biopharma SPRL, chemin du Foriest, 1420 Braine-l''Alleud, Belgium;3. Novartis Institutes of Biomedical Research, Novartis Pharma AG, PO Box CH-4002, Basel, Switzerland;4. Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland;5. Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany;6. Merz Pharmaceuticals GmbH, Alfred-Wegener-Str. 2, 60438 Frankfurt (Main), Germany;7. Dept. Preclin. Safety, AbbVie Deutschland GmbH & Co. KG, Knollstr., 67061 Ludwigshafen, Germany;8. Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany;9. Janssen, Global Safety Pharmacology, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium;10. Merck, Global Non Clinical Safety, Frankfurter Str. 250, 64293 Darmstadt, Germany |
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| Abstract: | The metabolism and mutagenicity of the esophageal carcinogen N-nitroso-N-methylaniline (NMA) was studied using hepatic and esophageal 9000 X g supernatant (S-9) preparations from Sprague-Dawley rats induced with pyrazole and phenobarbital. Only pyrazole-induced hepatic S-9 was able to dose-dependently activate NMA to a mutagen in the Ames assay and specifically in Salmonella typhimurium TA1537. NMA in the presence of phenobarbital-induced S-9 gave a very weak non-dose dependent mutagenic response. Metabolism of NMA by the two induced hepatic and esophageal S-9 fractions yielded aniline and N-methylaniline (MA). Phenobarbital-induced S-9 from both tissues also afforded phenol, while none was found with the pyrazole-induced preparations. Phenol formation presumably arose from the direct oxidative demethylation of NMA via a benzenediazonium ion (BDI) intermediate. The results indicate that an important metabolic pathway for NMA, with both inducing agents, entails an initial denitrosation to yield MA, which in turn rapidly undergoes oxidative demethylation to aniline. The conversion of NMA to phenol also suggests that direct demethylation of NMA in the phenobarbital-induced system is an important metabolic pathway. |
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