Metabolism of the Food-Borne Mutagen 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in Humans
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- 作者：Robert J. Turesky ; R. Colin Garner ; Dieter H. Welti ; Janique Richoz ; Steve H. Leveson ; Karen H. Dingley ; Kenneth W. Turteltaub ; and Laurent B. Fay
- 刊名：Chemical Research in Toxicology
- 出版年：1998
- 出版时间：March 1998
- 年：1998
- 卷：11
- 期：3
- 页码：217 - 225
- 全文大小：123K
- 年卷期：v.11,no.3(March 1998)
- ISSN：1520-5010
文摘
The metabolism of2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx) was investigatedin five human volunteers given a dietary equivalent of14C-labeled MeIQx. The amount of thedose excreted in urine ranged from 20.2% to 58.6%, with unmetabolizedMeIQx accounting for0.7-2.8% of the dose. Five principal metabolites were detectedin urine, and four of thederivatives were characterized by on-line UV spectroscopy and byHPLC-MS followingimmunoaffinity chromatography. Two metabolites were identified asthe phase II conjugatesN2-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamicacid (MeIQx-N2-SO3-)and N2-(
hars/beta2.gif" BORDER=0 ALIGN="middle">-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx-N2-Gl). Two othermetabolites were the cytochrome P450-mediated (P450) oxidation products2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline(8-CH2OH-MeIQx), andN2-(hars/beta2.gif" BORDER=0 ALIGN="middle">-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(NOH-MeIQx-N2-Gl). Thelatter product is a conjugate of the genotoxic metabolite2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline (NHOH-MeIQx). A largeinterindividual variation was observed in themetabolism and disposition of MeIQx; these four metabolites andunchanged MeIQx combinedaccounted for 6.3-26.7% of the total dose. The remainingprincipal metabolite found in allsubjects accounted for 7.6-28% of the dose. It has not beenpreviously identified in rodentsor nonhuman primates, and its structure remains unknown.P450-mediated ring oxidation ofMeIQx at the C-5 position, a major pathway of detoxication in rodents,was not detected inhumans. Both 8-CH2OH-MeIQx formation andNHOH-MeIQx formation are catalyzed by P4501A2 and may be useful biomarkers of P450 1A2 activity in humans.The levels of NHOH-MeIQx-N2-Gl found in human urine ranged from1.4% to 10.0% of the dose, which is significantlyhigher than that formed in rodents and nonhuman primates undergoingcancer bioassays.Thus, bioactivation of MeIQx by P450-mediated N-oxidation isextensive in humans.
hars/beta2.gif" BORDER=0 ALIGN="middle">-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx-N2-Gl). Two othermetabolites were the cytochrome P450-mediated (P450) oxidation products2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline(8-CH2OH-MeIQx), andN2-(hars/beta2.gif" BORDER=0 ALIGN="middle">-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(NOH-MeIQx-N2-Gl). Thelatter product is a conjugate of the genotoxic metabolite2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline (NHOH-MeIQx). A largeinterindividual variation was observed in themetabolism and disposition of MeIQx; these four metabolites andunchanged MeIQx combinedaccounted for 6.3-26.7% of the total dose. The remainingprincipal metabolite found in allsubjects accounted for 7.6-28% of the dose. It has not beenpreviously identified in rodentsor nonhuman primates, and its structure remains unknown.P450-mediated ring oxidation ofMeIQx at the C-5 position, a major pathway of detoxication in rodents,was not detected inhumans. Both 8-CH2OH-MeIQx formation andNHOH-MeIQx formation are catalyzed by P4501A2 and may be useful biomarkers of P450 1A2 activity in humans.The levels of NHOH-MeIQx-N2-Gl found in human urine ranged from1.4% to 10.0% of the dose, which is significantlyhigher than that formed in rodents and nonhuman primates undergoingcancer bioassays.Thus, bioactivation of MeIQx by P450-mediated N-oxidation isextensive in humans.