Identification of new 2-amino-3-methylimidazo[4,5-f]quinoline urinary metabolites from beta-naphthoflavone-treated mice.
Metabolism of the heterocyclic amine carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated in mice with and without 40 mg/kg beta-naphthoflavone (BNF). Following an oral dose of 40 mg/kg (14)C-IQ, a 24-h urine sample was collected. Metabolism was assessed by high-performance liquid chromatography, and metabolites were identified by electrospray ionization mass spectrometry. Three new metabolites were identified as 1,2-dihydro-2-amino-5-hydroxy-3-methylimidazo[4,5-f]quinoline (m/z 217, [M + H](+)), 1,2-dihydro-2-amino-5-O-glucuronide-3-methylimidazo[4,5-f]quinoline (m/z 393, [M + H](+)), and 1,2-dihydro-2-amino-5,7-dihydroxy-3-methylimidazo[4,5-f]quinoline (m/z 233, [M + H](+)). These metabolites represented 21% of the total urinary radioactivity recovered. For BNF-treated mice, the abundance of metabolites observed was 5-O-glucuronide > m/z 217 > m/z 393 > 5-sulfate > m/z 233 > N-glucuronide > demethyl-IQ > sulfamate. In control mice, metabolite urinary abundance was 5-O-glucuronide > demethyl-IQ > sulfamate > N-glucuronide > m/z 217 > 5-sulfate. In liver slices from BNF-treated mice, synthesis of m/z 217 and 5-O-glucuronide was significantly reduced by ellipticine, a cytochrome P450 (P450) inhibitor, whereas sulfamate synthesis was significantly increased and demethyl-IQ was unchanged. Liver microsomes from BNF-treated mice produced m/z 217 and demethyl-IQ, with the former inhibited by ellipticine and furafylline, a selective 1A2 inhibitor, and the latter by ellipticine only. Injection (intraperitoneal) of demethyl-IQ into BNF-treated mice resulted in only a 30% conversion to three metabolites that were not observed in urine from animals receiving IQ. Results from BNF-treated mice showed significant IQ metabolism by hepatic P450s. Therefore, differences in metabolism between mice treated with and without BNF may affect IQ tumorigenicity.
Lakshmi
Vijaya M
VM
Veterans Affairs Medical Center, St. Louis, MO 63125, USA.
Hsu
Fong-Fu
FF
Zenser
Terry V
TV
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003640:Dealkylation; D004611:Ellipticines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D007274:Injections, Intraperitoneal; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D021241:Spectrometry, Mass, Electrospray Ionization; D013431:Sulfates / Q000378:metabolism; D013451:Sulfonic Acids / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
D002250:Carbon Radioisotopes; D002273:Carcinogens; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004611:Ellipticines; D004791:Enzyme Inhibitors; D020719:Glucuronides; D011804:Quinolines; D013431:Sulfates; D013451:Sulfonic Acids; C034192:ellipticine; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019324:beta-Naphthoflavone; C005741:sulfamic acid; D013806:Theophylline; C050131:furafylline; D019388:Cytochrome P-450 CYP1A2