Characterization of new metabolites from in vivo biotransformation of 2-amino-3-methylimidazo[4,5-f]quinoline in mouse by mass spectrometry.
In studying the metabolic pathways underlying the mechanism of carcinogenesis of the heterocyclic amine of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), we recently found a new metabolite which gave an [M + H](+) ion of m/z 217 when subjected to electrospray ionization (ESI) in positive-ion mode. Following i.p. injection of this metabolite of m/z 217 (designated as m/z 217) to beta-naphthoflavone-treated mice, 57% of the total radioactivity was recovered in a 24-h mouse urine sample. HPLC separation followed by MS analysis indicates that the urine sample contained m/z 217 (36 +/- 3% of total recovered radioactivity) and two other peaks that gave rise to the [M + H](+) ions of m/z 393 (31 +/- 4%, designated as m/z 393) and m/z 233 (14 +/- 1%, designated as m/z 233). Beta-glucuronidase treatment of m/z 393 resulted in a radioactive peak corresponding to m/z 217. ESI in combination with various mass spectrometry techniques, including multiple-stage mass spectrometry, exact mass measurements and H/D exchange followed by tandem mass spectrometry, was used for structural characterization. The urinary metabolites of m/z 217, 393 and 233 were identified as 1,2-dihydro-2-amino-5-hydroxy-3-methylimidazo[4,5-f]quinoline, 1,2-dihydro-2-amino-5-O-glucuronide-3-methylimidazo[4,5-f]quinoline and 1,2-dihydro-2-amino-5,7-dihydroxy-3-methylimidazo[4,5-f]quinoline, respectively. Our results demonstrated that m/z 217 is biotransformed in vivo to m/z 393 by O-glucuronidation and to m/z 233 by oxidation. The observation of these more polar metabolites relative to IQ suggests that they may arise from a previously undescribed detoxification pathway.
Hsu
Fong-Fu
FF
Department of Medicine, Box 8127, Washington University School of Medicine, 660 S Euclid, St. Louis, Missouri 63110, USA. fhsu@im.wustl.edu
Lakshmi
Vijaya M
VM
Zenser
Terry V
TV
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D041961:Deuterium Exchange Measurement; D004790:Enzyme Induction; D005260:Female; D005965:Glucuronates / Q000737:chemistry; D020719:Glucuronides / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D006900:Hydroxylation; D006912:Hydroxyquinolines / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D007093:Imidazoles / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011804:Quinolines / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014556:Urine / Q000737:chemistry; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000378:metabolism
C545964:1,2-dihydro-2-amino-5,7-dihydroxy-3-methylimidazo(4,5-f)quinoline; C545963:1,2-dihydro-2-amino-5-O-glucuronide-3-methylimidazo(4,5-f)quinoline; C545962:1,2-dihydro-2-amino-5-hydroxy-3-methylimidazo(4,5-f)quinoline; D002273:Carcinogens; D005965:Glucuronates; D020719:Glucuronides; D006912:Hydroxyquinolines; D007093:Imidazoles; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019324:beta-Naphthoflavone