Stability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline.

2.50
Hdl Handle:
http://hdl.handle.net/10146/67739
Title:
Stability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline.
Authors:
Lakshmi, Vijaya M.; Hsu, Fong Fu; Schut, Herman A. J.; Zenser, Terry V.
Abstract:
2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible role in the initiation of colon cancer by MeIQx. 14C-N-NO-MeIQx (4 microM) was incubated for 4 h over a range of pH values, and its stability was monitored by HPLC. At pH values from pH 7.4 to 9.0, N-NO-MeIQx was very stable with no detectable change observed. Glutathione (1 mM) did not alter stability at pH 7.4. As the pH decreased, this nitrosamine was less stable with only 48 +/- 1% remaining at pH 5.5 and none remaining at pH 3.5 or 2.0. Major products identified by electrospray ionization mass spectrometry were 3,8-dimethylimidazo[4,5-f]quinoxaline and 2-hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline. MeIQx was a minor product. At pH 2.0, the t(1/2) for N-NO-MeIQx was reduced from 2.1 +/- 0.2 to 1.2 +/- 0.1 min with 10 mM NaN3. This effect of azide was due to the formation of 2-azido-MeIQx. The binding of 14C-N-NO-MeIQx to DNA increased with decreasing pH. The 10-fold increase in binding observed at pH 2.0 as compared to pH 5.5 was completely inhibited by 10 mM NaN3 due to 2-azido-MeIQx formation. The reactivity of N-NO-MeIQx was compared to N-OH-MeIQx by evaluating adduct formation with 2'-deoxyguanosine 3'-monophosphate (dGp) by 32P-postlabeling. N-OH-MeIQx formed a single major adduct, N-(deoxyguanosin-8-yl)-MeIQx (dG-C8-MeIQx). Incubation of N-NO-MeIQx under inflammatory conditions (pH 5.5 +/- HOCl) produced dG-C8-MeIQx along with 4-6 other adducts. dG-C8-MeIQx formation increased in the presence of HOCl. Liver from a MeIQx-treated mouse contained dG-C8-MeIQx and two other adducts detected with N-NO-MeIQx but not N-OH-MeIQx. These results suggest that N-NO-MeIQx could be genotoxic, is activated by conditions that mediate inflammatory responses, and is a possible cancer risk factor for individuals with inflammation of the colon.
Citation:
Chem. Res. Toxicol. 2006, 19 (2):325-333
Journal:
Chemical research in toxicology
Issue Date:
Feb-2006
URI:
http://hdl.handle.net/10146/67739
DOI:
10.1021/tx050305x
PubMed ID:
16485910
Additional Links:
http://pubs.acs.org/doi/abs/10.1021/tx050305x; http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16485910
Type:
Article
Language:
en
Description:
KEYWORDS - CLASSIFICATION: administration & dosage;Animals;chemistry;Chromatography,High Pressure Liquid;drug effects;Dna;DNA Adducts;Dose-Response Relationship,Drug;Glutathione;Hydrogen-Ion Concentration;isolation & purification;Imidazoles;Liver;Male;mechanisms of carcinogenesis;Mice;Mice,Inbred C57BL;Nitrosamines;pharmacology;Quinoxalines;Research;Sensitivity and Specificity;Spectrometry,Mass,Electrospray Ionization;Time Factors.
ISSN:
0893-228X
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorLakshmi, Vijaya M.-
dc.contributor.authorHsu, Fong Fu-
dc.contributor.authorSchut, Herman A. J.-
dc.contributor.authorZenser, Terry V.-
dc.date.accessioned2009-05-11T08:54:04Z-
dc.date.available2009-05-11T08:54:04Z-
dc.date.issued2006-02-
dc.identifier.citationChem. Res. Toxicol. 2006, 19 (2):325-333en
dc.identifier.issn0893-228X-
dc.identifier.pmid16485910-
dc.identifier.doi10.1021/tx050305x-
dc.identifier.urihttp://hdl.handle.net/10146/67739-
dc.descriptionKEYWORDS - CLASSIFICATION: administration & dosage;Animals;chemistry;Chromatography,High Pressure Liquid;drug effects;Dna;DNA Adducts;Dose-Response Relationship,Drug;Glutathione;Hydrogen-Ion Concentration;isolation & purification;Imidazoles;Liver;Male;mechanisms of carcinogenesis;Mice;Mice,Inbred C57BL;Nitrosamines;pharmacology;Quinoxalines;Research;Sensitivity and Specificity;Spectrometry,Mass,Electrospray Ionization;Time Factors.en
dc.description.abstract2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible role in the initiation of colon cancer by MeIQx. 14C-N-NO-MeIQx (4 microM) was incubated for 4 h over a range of pH values, and its stability was monitored by HPLC. At pH values from pH 7.4 to 9.0, N-NO-MeIQx was very stable with no detectable change observed. Glutathione (1 mM) did not alter stability at pH 7.4. As the pH decreased, this nitrosamine was less stable with only 48 +/- 1% remaining at pH 5.5 and none remaining at pH 3.5 or 2.0. Major products identified by electrospray ionization mass spectrometry were 3,8-dimethylimidazo[4,5-f]quinoxaline and 2-hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline. MeIQx was a minor product. At pH 2.0, the t(1/2) for N-NO-MeIQx was reduced from 2.1 +/- 0.2 to 1.2 +/- 0.1 min with 10 mM NaN3. This effect of azide was due to the formation of 2-azido-MeIQx. The binding of 14C-N-NO-MeIQx to DNA increased with decreasing pH. The 10-fold increase in binding observed at pH 2.0 as compared to pH 5.5 was completely inhibited by 10 mM NaN3 due to 2-azido-MeIQx formation. The reactivity of N-NO-MeIQx was compared to N-OH-MeIQx by evaluating adduct formation with 2'-deoxyguanosine 3'-monophosphate (dGp) by 32P-postlabeling. N-OH-MeIQx formed a single major adduct, N-(deoxyguanosin-8-yl)-MeIQx (dG-C8-MeIQx). Incubation of N-NO-MeIQx under inflammatory conditions (pH 5.5 +/- HOCl) produced dG-C8-MeIQx along with 4-6 other adducts. dG-C8-MeIQx formation increased in the presence of HOCl. Liver from a MeIQx-treated mouse contained dG-C8-MeIQx and two other adducts detected with N-NO-MeIQx but not N-OH-MeIQx. These results suggest that N-NO-MeIQx could be genotoxic, is activated by conditions that mediate inflammatory responses, and is a possible cancer risk factor for individuals with inflammation of the colon.en
dc.language.isoenen
dc.relation.urlhttp://pubs.acs.org/doi/abs/10.1021/tx050305xen
dc.relation.urlhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16485910en
dc.subject.meshAnimals-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshDNA-
dc.subject.meshDNA Adducts-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshHydrogen-Ion Concentration-
dc.subject.meshImidazoles-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshNitrosamines-
dc.subject.meshQuinoxalines-
dc.subject.meshSensitivity and Specificity-
dc.subject.meshSpectrometry, Mass, Electrospray Ionization-
dc.subject.meshTime Factors-
dc.titleStability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline.en
dc.typeArticleen
dc.identifier.journalChemical research in toxicologyen
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