Turesky R J, Garner R C, Welti D H, Richoz J, Leveson S H, Dingley K H, Turteltaub K W, Fay L B
Nestlé Research Center, Nestec Ltd., Lausanne, Switzerland.
Chem Res Toxicol. 1998 Mar;11(3):217-25. doi: 10.1021/tx9701891.
The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in five human volunteers given a dietary equivalent of 14C-labeled MeIQx. The amount of the dose excreted in urine ranged from 20.2% to 58.6%, with unmetabolized MeIQx accounting for 0.7-2.8% of the dose. Five principal metabolites were detected in urine, and four of the derivatives were characterized by on-line UV spectroscopy and by HPLC-MS following immunoaffinity chromatography. Two metabolites were identified as the phase II conjugates N2-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid (MeIQx-N2-SO3(-)) and N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx-N2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and N2-(beta-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidaz o[4,5-f]quinoxaline (NOH-MeIQx-N2-Gl). The latter product is a conjugate of the genotoxic metabolite 2-(hydroxyamino)-3,8-dimethylimidazo-[4,5-f]quinoxaline (NHOH-MeIQx). A large interindividual variation was observed in the metabolism and disposition of MeIQx; these four metabolites and unchanged MeIQx combined accounted for 6.3-26.7% of the total dose. The remaining principal metabolite found in all subjects accounted for 7.6-28% of the dose. It has not been previously identified in rodents or nonhuman primates, and its structure remains unknown. P450-mediated ring oxidation of MeIQx at the C-5 position, a major pathway of detoxication in rodents, was not detected in humans. Both 8-CH2OH-MeIQx formation and NHOH-MeIQx formation are catalyzed by P450 1A2 and may be useful biomarkers of P450 1A2 activity in humans. The levels of NHOH-MeIQx-N2-Gl found in human urine ranged from 1.4% to 10.0% of the dose, which is significantly higher than that formed in rodents and nonhuman primates undergoing cancer bioassays. Thus, bioactivation of MeIQx by P450-mediated N-oxidation is extensive in humans.
在五名人类志愿者中研究了2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）的代谢情况，这些志愿者摄入了相当于膳食水平的14C标记的MeIQx。尿液中排出的剂量占比在20.2%至58.6%之间，未代谢的MeIQx占剂量的0.7 - 2.8%。在尿液中检测到了五种主要代谢物，其中四种衍生物通过在线紫外光谱以及免疫亲和色谱后的高效液相色谱 - 质谱联用进行了表征。两种代谢物被鉴定为II相缀合物N2 - (3,8 - 二甲基咪唑并[4,5 - f]喹喔啉 - 2 - 基)氨基磺酸（MeIQx - N2 - SO3(-)）和N2 - (β - 1 - 葡萄糖醛酸基)-2 - 氨基 - 3,8 - 二甲基咪唑并[4,5 - f]喹喔啉（MeIQx - N2 - Gl）。另外两种代谢物是细胞色素P450介导（P450）的氧化产物2 - 氨基 - 8 - (羟甲基)-3 - 甲基咪唑并[4,5 - f]喹喔啉（8 - CH2OH - MeIQx）和N2 - (β - 1 - 葡萄糖醛酸基)-N - 羟基 - 2 - 氨基 - 3,8 -二甲基咪唑并[4,5 - f]喹喔啉（NOH - MeIQx - N2 - Gl）。后一种产物是遗传毒性代谢物2 - (羟基氨基)-3,8 - 二甲基咪唑并[4,5 - f]喹喔啉（NHOH - MeIQx）的缀合物。在MeIQx的代谢和处置过程中观察到了较大的个体间差异；这四种代谢物和未变化的MeIQx合起来占总剂量的6.3% - 26.7%。在所有受试者中发现的其余主要代谢物占剂量的7.6% - 28%。它之前在啮齿动物或非人类灵长类动物中未被鉴定出来，其结构仍然未知。在啮齿动物中作为主要解毒途径的MeIQx在C - 5位的P450介导的环氧化在人类中未被检测到。8 - CH2OH - MeIQx的形成和NHOH - MeIQx的形成均由P450 1A2催化，可能是人类中P450 1A2活性的有用生物标志物。在人类尿液中发现NHOH - MeIQx - N2 - Gl的水平占剂量的1.4%至10.0%，这显著高于进行癌症生物测定的啮齿动物和非人类灵长类动物中形成的水平。因此，P450介导的N - 氧化对MeIQx的生物活化在人类中很广泛。
