title: Metabolism and excretion of 1-hydroxymethylpyrene, the proximate metabolite of the carcinogen 1-methylpyrene, in rats.
abstract: 1-Methylpyrene, an alkylated polycyclic aromatic hydrocarbon and environmental carcinogen, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1-HMP) and subsequent sulfo conjugation to the DNA-reactive 1-sulfooxymethylpyrene. In addition to the bioactivation, processes of metabolic detoxification and transport greatly influence the genotoxicity of 1-methylpyrene. For a better understanding of 1-HMP detoxification in vivo we studied urinary and fecal metabolites in rats following intraperitoneal doses of 19.3mg 1-HMP/kg body weight (5 rats) or the same dose containing 200μCi [(14)C]1-HMP/kg body weight (2 rats). After 48h, 48.0% (rat 1) and 29.1% (rat 2) of the radioactivity was recovered as 1-HMP in the feces. Six major metabolites were observed by UV and on-line radioactivity detection in urine samples and feces after HPLC separation. The compounds were characterized by mass spectrometry, (1)H NMR and (1)H-(1)H COSY NMR spectroscopy, which allowed assigning tentative molecular structures. Two prominent metabolites, 1-pyrene carboxylic acid (M-6) and the acyl glucuronide of 1-pyrene carboxylic acid (M-5) accounted for 17.7% (rat 1) and 25.2% (rat 2) of the overall radioactive dose. Further, we detected the acyl glucuronide of 6-hydroxy-1-pyrene carboxylic acid (M-1) and 8-sulfooxy-1-pyrene carboxylic acid (M-3) together with two regioisomers of M-3 (M-2 and M-4) differing in position of the sulfate group at the pyrene ring. In urine samples, the radioactivity of 1-pyrene carboxylic acid and its five derivatives amounted to 32.4% (rat 1) or 45.5% (rat 2) of the total [(14)C]1-HMP dose.
authors: Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany. Electronic address: carolin.bendadani@bvl.bund.de.
authors: Carolin
authors: C
authors: Bendadani
authors: Institute of Organic Chemistry, University of Tuebingen, 72076 Tuebingen, Germany. Electronic address: steinhauser.lisa@gmail.com.
authors: Lisa
authors: L
authors: Steinhauser
authors: Institute of Organic Chemistry, University of Tuebingen, 72076 Tuebingen, Germany. Electronic address: heidi.albert@gmx.de.
authors: Klaus
authors: K
authors: Albert
authors: Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany; Department of Food Safety, Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany. Electronic address: hansruedi.glatt@bfr.bund.de.
authors: Hansruedi
authors: H
authors: Glatt
authors: Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany; Department of Food Safety, Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany. Electronic address: bernhard.monien@bfr.bund.de.
authors: Bernhard H
authors: BH
authors: Monien
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism / Q000652:urine; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011721:Pyrenes / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
chemical_list: C530676:1-pyrenecarboxylic acid; D002264:Carboxylic Acids; D002273:Carcinogens; D011721:Pyrenes; C102088:1-sulfooxymethylpyrene; C053035:1-methylpyrene; C065833:1-hydroxymethylpyrene
keywords: 1-Hydroxymethylpyrene; 1-Methylpyrene; Alkylated polycyclic aromatic hydrocarbons; Rat metabolism