2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶 | 105650-23-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶
• 中文别名: 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶
• 英文名称: 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine
• 英文别名: PhIP；2-amino-1-methyl-6-phenylimidazo<4,5-b>pyridine；2-amino-1-methyl-6-phenylimidazo<4,5-f>pyridine；[3H]-2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine；1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine；2-amino-1-methyl-6-phenylimidazolo[4,5-b]pyridine；2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine；1-methyl-6-phenylimidazo[4,5-b]pyridin-2-amine
• CAS: 105650-23-5
• 化学式: C₁₃H₁₂N₄
• mdl: MFCD00210745
• 分子量: 224.265
• InChiKey: UQVKZNNCIHJZLS-UHFFFAOYSA-N

物化性质

• 熔点：
  300
• 沸点：
  355.66°C (rough estimate)
• 密度：
  1.2067 (rough estimate)
• 溶解度：
  DMF：10mg/mL； DMSO：10mg/mL；乙醇：15mg/mL；乙醇:PBS (pH 7.2) (1:3): 0.25 mg/ml
• 物理描述：
  Solid
• 颜色/状态：
  Gray-white crystals
• 蒸汽压力：
  8.09X10-9 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition, it emits toxic vapors of /nitrogen oxides/.
• 解离常数：
  pKa1 = 2.12 (secondary amine); pKa2 = 5.43 (secondary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.076
• 拓扑面积：
  56.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

该研究旨在评估十字花科蔬菜摄入对20名非吸烟白人男性受试者PhIP（杂环胺）代谢的影响。研究包括三个为期12天的阶段，即两个避免摄入十字花科蔬菜的阶段（第1和第3阶段）和一个高十字花科蔬菜饮食期（第2阶段），受试者每天摄入250克球芽甘蓝和西兰花。每个研究阶段结束时，受试者摄入含有4.90微克PhIP的熟肉餐，并收集长达48小时的尿液样本。十字花科蔬菜的摄入显著提高了肝脏CYP1A2的活性，这是通过唾液中咖啡因动力学的变化来证明的。在第1和第3阶段，0-48小时尿液样本中N(2)-羟基-N(2)-PhIP-葡萄糖醛酸苷的排泄量是N(2)-羟基-PhIP-N(3)-葡萄糖醛酸苷的六倍。十字花科蔬菜的摄入显著增加了0-48小时尿液样本中N(2)-羟基-PhIP-N(2)-葡萄糖醛酸苷的排泄量，分别达到第1和第3阶段观察水平的127%和136%。相比之下，N(2)-羟基-PhIP-N(3)-葡萄糖醛酸苷的尿排泄量没有变化。在第1和第3阶段，两种PhIP代谢物的尿排泄量大约占PhIP剂量的39%，而在第2阶段，它们大约占剂量的49%。这项研究表明，十字花科蔬菜的摄入可以在人类中诱导PhIP的I相和II相代谢。

The aim of this study was to evaluate the effect of cruciferous vegetable consumption on the metabolism of PhIP in 20 non-smoking Caucasian male subjects. The study consisted of three 12-day phases, namely two periods of avoidance of cruciferous vegetables (phases 1 and 3) and a high cruciferous vegetable diet period (phase 2), when subjects ingested 250 g each of Brussels sprouts and broccoli per day. At the end of each study phase, the subjects consumed a cooked meat meal containing 4.90 ug PhIP and urine samples were collected for up to 48 h. Cruciferous vegetable consumption significantly increased hepatic CYP1A2, as demonstrated by changes in saliva caffeine kinetics. ... In phases 1 and 3, the excretion of N(2)-hydroxy-N(2)-PhIP-glucuronide in 0-48 hr urine samples was six times that of N(2)-hydroxy-PhIP-N(3)-glucuronide. Cruciferous vegetable consumption significantly increased the urinary excretion of N(2)-hydroxy-PhIP-N(2)-glucuronide in 0-48 hr urine samples to 127 and 136% of levels observed in phases 1 and 3, respectively. In contrast, the urinary excretion of N(2)-hydroxy-PhIP-N(3)-glucuronide was unchanged. While the urinary excretion of both PhIP metabolites accounted for approximately 39% of the PhIP dose in phases 1 and 3, they accounted for approximately 49% of the dose in phase 2. This study demonstrates that cruciferous vegetable consumption can induce both the phase I and II metabolism of PhIP in humans.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Fischer 344雄性大鼠单次给予0.03-30 mg/kg的(2-14)C-2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶((14C)PhIP)，在48小时内测定尿液和粪便中的放射性，并鉴定和量化主要代谢物。剂量对尿液中代谢物轮廓的影响很小，但确实影响了粪便中的轮廓。PhIP在高剂量下代谢更有效率。此外，在大鼠单次给予(14)C-PhIP之前，先用Aroclor 1254（PCB）、3-甲基胆蒽（MC）、苯巴比妥（PB）、PhIP和玉米油预处理，并与只接受(14)C-PhIP的对照组进行比较。对每个组的尿液和粪便中的主要代谢物进行了量化，以及PhIP与血清蛋白、血红蛋白和选定组织的结合。MC和PCB预处理导致PhIP的4'-羟基化增加，尿液中N-羟基化代谢物的量减少。PB预处理导致尿液中N-羟基化代谢物的量增加，但4'-羟基化减少。MC或PCB预处理导致PhIP与肝脏和肾脏的结合增加，而减少其他组织的结合。PhIP预处理的动物与未处理组相比几乎没有显著差异，而PB预处理通常导致组织中PhIP结合的减少。

Male Fischer 344 rats were given a single dose of 0.03-30 mg/kg of (2-14)C-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ((14C)PhIP), the radioactivity in urine and feces was determined over 48 hr, and the major metabolites were identified and quantified. Dose had little effect on the profile of metabolites in the urine but did influence the profile in the feces. PhIP was more efficiently metabolized at higher doses. In addition, rats were pretreated with Aroclor 1254 (PCB), 3-methylcholanthrene (MC), phenobarbital (PB), PhIP and corn oil prior to a single dose of (14)C-PhIP, and compared with a control group receiving (14)C-PhIP only. The major metabolites in the urine and feces were quantitated for each group, as well as PhIP binding to serum proteins, hemoglobin and selected tissues. Pretreatment with MC and PCB resulted in an increase in the amount of 4'-hydroxylation of PhIP and a decrease in the amount of N-hydroxylated metabolites in the urine. Pretreatment with PB resulted in an increase in the amount of N-hydroxylated metabolites, but a decrease in 4'-hydroxylation. Pretreatment with either MC or PCB resulted in an increase in PhIP binding to the liver and kidney, while reducing the binding in other tissues. Animals pretreated with PhIP showed few significant differences from the untreated group, while pretreatment with PB in general resulted in a decrease of PhIP binding in tissues.

来源:Hazardous Substances Data Bank (HSDB)

代谢

腺瘤性息肉病基因(APC)产物功能的丧失是人类结直肠癌发生早期的频繁事件。正常(Apc(+/+))和癌前(Apc(Min/+), Min=多发性肠肿瘤)的小鼠结肠上皮细胞可用于研究致癌作用的促进...研究了这两种小鼠细胞系中(14)C-PhIP的代谢。经2,3,7,8-四氯二苯并-p-二恶英(TCDD)诱导的细胞将PhIP代谢为4'-OH-PhIP作为主要的解毒代谢物。此外，还鉴定出了5-OH-PhIP，揭示了中间反应代谢物的形成，因为它来自N-乙酰氧基-PhIP结合物的降解。Apc(Min/+)细胞产生显著更高量的这些代谢物。还观察到了去甲基化代谢物，表明结肠含有显著依赖于CYP1家族的代谢活性。在Apc(Min/+)细胞中观察到少量的羟基葡萄糖苷酸-PhIP代谢物，葡萄糖苷酸化是解毒途径中一个重要步骤。定量实时逆转录聚合酶链反应实验表明，TCDD诱导在Apc(Min/+)细胞中CYP1A1、CYP1A2和CYP1B1基因表达上具有主导作用。在这些细胞中，N-乙酰转移酶-2的表达水平也更高。因此，Apc(Min/+)细胞中代谢生物激活PhIP的更重要潜力可以与生成新的原位突变的高概率相关联。

... Loss of function of the adenomatous polyposis coli (APC) gene product is an early and frequent event in human colorectal carcinogenesis. Normal (Apc(+/+)) and pre-malignant (Apc(Min/+), where Min=multiple intestinal neoplasia) colonic epithelial cells of mice can be used to study promotion of carcinogenesis ... The metabolism of (14)C-PhIP /was investigated/ in these two murine cell lines. Cells induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) metabolized PhIP into 4'-OH-PhIP as the main metabolite in PhiP detoxification. Besides, 5-OH-PhIP was identified, revealing the formation of intermediary reactive metabolites, since it results from a degradation of conjugates of N-acetoxy-PhIP. Apc(Min/+) cells produce significantly higher amounts of these metabolites. Demethylated metabolites are also observed, indicating that the colon contains a significant CYP1 family dependent metabolic activity. A minor hydroxy-glucuronide-PhIP metabolite is observed in Apc(Min/+) cells, the glucuronidation being known as an important step in the detoxification pathway. Quantitative real-time reverse transcription polymerase chain reaction experiments demonstrate that induction by TCDD has prevailing effects in gene expression of CYP1A1, CYP1A2 and CYP1B1 in Apc(Min/+) cells. In these cells, N-acetyltransferase-2 is also expressed at higher levels. So, the more important potency to metabolically bio-activate PhIP, as measured in Apc(Min/+) cells, can be linked to a higher probability to generate new in situ mutations.

来源:Hazardous Substances Data Bank (HSDB)

代谢

研究了2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）在小鼠体内的代谢。在3-甲基胆蒽诱导的小鼠中，经腹腔注射0.1、1.0和10 mg/kg的(14C)PhIP后，24小时内尿液和粪便中的排出量分别占剂量的16%和42-56%。原形药物在尿液中的排出量仅占给药剂量的0.5-0.8%。在所有剂量下，主要的尿液代谢物被鉴定为4'-(2-氨基-1-甲基咪唑[4,5-b]吡啶-6-基)苯磺酸盐，这种代谢物约占剂量的5%。未经诱导的小鼠以磺酸结合物的形式排出了超过10 mg/kg剂量的13%。与诱导小鼠相比，未经诱导的小鼠尿液中2-氨基-1-甲基-6-(4'-羟基)-苯基咪唑[4,5-b]吡啶（4'-羟基-PhIP）和2-羟基氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（N-羟基-PhIP）的葡萄糖醛酸苷结合物的排出量也较高（4倍）。诱导后尿液中原型代谢物排出的减少与肝脏微粒体制备中代谢物形成的增加形成对比。与未经诱导相比，诱导的微粒体在50 uM (3)H-PhIP的孵育中产生的4'-羟基-PhIP和N-羟基-PhIP的量分别几乎高出7倍和3倍。在浓度小于10 uM时，PhIP几乎完全由诱导的制备物转化为一种未识别的代谢物，这种代谢物不会被C18柱保留。这种代谢物在4'-羟基-PhIP或N-羟基-PhIP的孵育中也会形成，但未经诱导的动物微粒体产生的速度要慢得多。(3)H-PhIP与微粒体蛋白的共价结合在孵育中是浓度依赖性的，诱导的制备物比未经诱导的制备物高2到4倍。诱导小鼠给予(14)C-PhIP后，肝脏和肾脏的共价结合是剂量依赖性的。在10 mg/kg的PhIP剂量下，诱导小鼠的肝脏中产生的加合物的水平比未经诱导的小鼠高1.7倍，但未经诱导的动物肾脏的结合更高。这些研究表明，细胞色素P450和其他外源化学物酶在PhIP的代谢、分布和激活中的重要性。

The metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) ... was investigated in mice. In 3-methylcholanthrene-induced mice administered 0.1, 1.0, and 10 mg/kg (14C)PhIP (ip), urinary and fecal excretion over 24 hr accounted for 16% and 42-56% of the dose respectively. Urinary excretion of unchanged parent compound accounted for only 0.5-0.8% of the administered dose. At all doses, the major urinary metabolite was identified as 4'-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate and this metabolite comprised approximately 5% of the dose. Uninduced mice excreted greater than 13% of a 10 mg/kg dose as the sulfate conjugate. Urinary excretion of both 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP) and a glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (N-hydroxy-PhIP) was also higher (4-fold) in uninduced versus induced mice. The decreased urinary excretion of P450-derived metabolites via induction contrasted with increased metabolite formation by hepatic microsomal preparations. 4'-Hydroxy-PhIP and N-hydroxy-PhIP were produced in amounts nearly 7- and 3-fold higher respectively by induced versus uninduced microsomal incubations at 50 uM (3)H-PhIP. At concentrations less than 10 uM, PhIP was almost exclusively converted by the induced preparations to an unidentified metabolite that was not retained by the C18 column. This metabolite, which also was formed in incubations with either 4'-hydroxy-PhIP or N-hydroxy-PhIP, was produced by microsomes from uninduced animals at a much slower rate. Covalent binding to microsomal protein in incubations with (3)H-PhIP was concentration-dependent and 2- to 4-fold higher in induced than uninduced preparations. Covalent binding in liver and kidney of induced mice administered (14)C-PhIP was dose dependent. At 10 mg/kg PhIP, adducts were produced at 1.7-fold higher levels in livers of induced versus uninduced mice, but renal binding was higher in uninduced animals. These studies indicate the importance of cytochrome P450 and other xenobiotic enzymes in the metabolism, disposition and activation of PhIP.

来源:Hazardous Substances Data Bank (HSDB)

代谢

2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶已知的人体代谢物包括2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶和N2-葡萄糖苷酸。

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine has known human metabolites that include 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, N2-glucuronide.

来源:NORMAN Suspect List Exchange

毒理性

• 致癌性证据

PhIP（2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶）可能对人类致癌（2B组）。

There is inadequate evidence in humans for the carcinogenicity of PhIP. There is suffcient evidence in experimental animais for the carcinogenicity of PhIP. Overall evaluation: PhIP (2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) is possibly carcinogenic to humans (Group 2B).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

PhIP合理地被预期为一种人类致癌物，基于在实验动物中充分的致癌性证据和支持性的遗传毒性数据。[美国卫生与公共服务部/国家毒理学计划；第十一份致癌物报告：2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶]

PhIP is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals and supporting genotoxicity data.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-1-Methyl-6-Phenylimidazo

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：PhIP

IARC Carcinogenic Agent:PhIP

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第56卷：（1993年）一些自然存在的物质：食品成分和构成要素，杂环芳香胺和霉菌毒素

IARC Monographs:Volume 56: (1993) Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

Fischer 344 大鼠通过灌胃给予单次剂量为 0.60 毫克/只的 (2-14)C-2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶 (PhIP)；并在给药后 12、24、48 和 96 小时测定粪便、尿液、血液、血清蛋白、血红蛋白和组织中的放射性含量。在尿液中发现了 一个主要和四个次要的含放射性组分，在粪便中发现了 一个主要和两个次要的含放射性组分。粪便 是排泄的主要途径，在最初的 24 小时内代表了剂量的 78%，粪便中未变化的 PhIP 占剂量的 51%。未代谢的 PhIP 也被显示为通过腹腔注射单次给药的动物胆汁和粪便中的主要放射性组分。血液含有剂量的一个小部分，而血液中 PhIP 的主要、持久结合形式是血红蛋白。在给药后 12 小时，结肠和盲肠含有最高的放射性浓度，而在较晚的时间点肾脏和肝脏显示出最高的浓度。在 24 小时后的时间点，组织中含有的放射性有 80-90% 是乙醇不溶的，这表明它已与 macromolecules 共价结合。

Fischer 344 rats were given a single dose of 0.60 mg/animal of (2-14)C-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by gavage; and radioactivity contained in feces, urine, blood, serum proteins, hemoglobin, and tissues was determined at 12, 24, 48, and 96 hr after dosing. One major and four minor radioactivity-containing fractions were found in the urine and one major and two minor radioactivity-containing fractions were found in the feces. The feces was the major route of excretion, representing 78% of dose during the first 24 hr, and unchanged PhIP in the feces accounted for 51% of the dose. Unmetabolized PhIP was also shown to be the major radioactive fraction in bile and feces from animals given a single dose by ip injection. Blood contained a small fraction of the dose and the major, persistently-bound form of PhIP in the blood was to hemoglobin. At 12 hr after administration of the dose the colon and cecum contained the highest concentration of radioactivity, while at later times the kidney and liver showed the highest concentration. Of the tissue-contained radioactivity 80-90% was ethanol insoluble at time points later than 24 hr, suggesting that it was covalently bound to macromolecules.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 使用加速器质谱法提供的灵敏度，研究了在人类饮食等效剂量下PhIP的生物利用度和命运。将(2-14)C-PhIP通过灌胃给C57BL/6雄性小鼠（41 ng/kg）。在随后的96小时内收集组织和排泄物。在整个研究期间，给药剂量的100%通过尿液（90%）和粪便（10%）排出。放射性碳标记的PhIP从胃肠道的吸收是迅速的，放射性碳水平在暴露后1小时内在全血和尿液中达到峰值。粪便中的(14)C水平在12小时达到峰值。组织水平在3小时达到峰值，放射性标记的最高浓度在大肠、胃和肝脏，其次是肾脏、胰腺、肺和脾脏。在暴露48-96小时后，可以在组织中检测到PhIP的(14)C低水平（给药剂量的0.01-0.04%），可能是由于与蛋白质或DNA的共价结合。计算得出，在这个剂量下PhIP的半衰期为1.14小时。

... The bioavailability and fate of /PhIP/ at a human dietary equivalent dose /was examined/ using the high sensitivity offered by accelerator mass spectrometry. (2-14)C-PhIP was administered to C57BL/6 male mice (41 ng/kg) by gavage. Tissues and excreta were collected over the subsequent 96 hr. 100% of the administered dose was excreted in urine (90%) and feces (10%) over the length of the study. Absorption of the radiocarbon-tagged PhIP from the gastrointestinal tract was rapid, with radiocarbon levels peaking in the whole blood and urine within 1 hr of exposure. Fecal (14)C levels peaked at 12 hr. Tissue levels peaked by 3 hr with the highest concentrations of radiolabel in the intestine, stomach, and liver, followed by the kidney, pancreas, lung, and spleen. Low levels of (14)C from PhIP (0.01-0.04% of the administered dose) could be detected in the tissues 48-96 hr after exposure, possibly due to covalent binding to protein or DNA. The calculated half-life of PhIP at this dose was 1.14 hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 对怀孕或哺乳期的C57Bl/6小鼠单次腹腔注射PhIP（剂量为4.7-5.2 mg/kg体重）后，通过组织提取和高效液相色谱（HPLC）分析研究了PhIP向胎儿和新生儿的转移。证明了PhIP未改变地通过胎盘转移给胎儿；在妊娠晚期观察到胎儿体内的PhIP水平最高。在妊娠晚期对注射了(2-14)C-PhIP（1.4 mg/kg）的小鼠进行放射自显影，结果显示放射性物质在胎儿眼睛的色素部分高度且选择性地积聚，胎儿肝脏、胃肠道内容物、尿液和子宫液中也观察到中等水平的放射性。对暴露于哺乳期母鼠4小时的新生小鼠的胃内容物和组织进行HPLC分析，显示出未改变的PhIP的存在，这提示PhIP可能通过母鼠的乳汁排出。本研究的结果引起了人们对孕期和哺乳期接触PhIP可能会导致这种食物诱变剂转移到胎儿和婴儿的担忧。

... The transfer of PhIP to fetuses and neonates following a single ip dose (4.7-5.2 mg/kg bw) to pregnant or lactating C57Bl/6 mice was studied by tissue extraction and HPLC analysis. A transplacental transfer of unchanged (3)H-PhIP to fetuses was demonstrated; the highest fetal levels were observed at late gestation. Autoradiography of mice injected iv with (2-14)C-PhIP (1.4 mg/kg) during late gestation showed a high and selective localization of radioactivity in the pigmented parts of the fetal eye and a moderate level of radioactivity in the fetal liver, gastro-intestinal contents, urine and in the uterine fluid. HPLC analysis of stomach contents and tissues of newborn mice exposed for 4 hr to lactating dams dosed ip with (3)H-PhIP (5.2 mg/kg) showed the presence of unchanged PhIP suggesting excretion of PhIP in the milk of the dams. The results in this study raise concern that exposure to PhIP during pregnancy and nursing may result in a transfer of this food mutagen to fetuses and infants.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

烹饪肉类、鱼类或家禽时高温会产生杂环芳基胺（HAAs），这些物质可能会被代谢激活为致突变或致癌中间体。细胞色素P4501A2（CYP1A2）和N-乙酰转移酶（NAT2）是在这些生物转化中主要涉及的酶...研究确定了两酶活性与尿液中未代谢和II期结合物MeIQx（2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉）和PhIP（2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶）排泄量的关系，研究对象为食用含有已知量MeIQx和PhIP的高温烹饪肉类的统一饮食人群。研究对象在进食后0-12小时和12-24小时收集尿液。通过酸处理尿液来定量水解II期结合物到相应的母胺，然后测量尿液中的MeIQx和PhIP。含有HAAs的提取物通过免疫亲和色谱纯化，并使用液相色谱-电喷雾串联质谱分析。0-12小时尿液中MeIQx含量在酸水解后增加了3-21倍。经过酸处理后，0-12小时尿液中MelQx（未代谢加上N2-葡萄糖苷酸和磺酰胺代谢物）的总排泄量为剂量的10.5 +/- 3.5%（平均值+/-标准差），而0-12小时期间PhIP（未代谢加上酸不稳定的结合物）的总量为剂量的4.3 +/- 1.7%（平均值+/-标准差）。12-24小时尿液中PhIP的总量在酸处理后为剂量的0.9 +/- 0.4%（平均值+/-标准差）。对所有对象在0-12小时期间排泄的MeIQx和PhIP量（占摄入剂量的百分比）进行线性回归分析，得到低度但显著的相关性（r = 0.37, P = 0.005）。线性回归分析显示，尿液中MeIQx总量（未代谢加上N2-葡萄糖苷酸和磺酰胺代谢物）较低与CYP1A2活性较高有关，而尿液中PhIP总量（未代谢加上结合物）与CYP1A2活性无关。这些结果表明，在人类中，MeIQx的代谢和处置比PhIP更受CYP1A2活性的影响。线性回归分析未发现NAT2活性与尿液中MeIQx或PhIP（未代谢加上酸不稳定的结合物）水平有关。

Cooking meat, fish, or poultry at high temperature gives rise to heterocyclic aromatic amines (HAAs), which may be metabolically activated to mutagenic or carcinogenic intermediates. The enzymes cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2) are principally implicated in such biotransformations ... The relationship between the activity of these two enzymes and the urinary excretion of unmetabolized and Phase II conjugates of the two HAAs MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) /was determined/ in individuals fed a uniform diet containing high-temperature cooked meat. The subjects in the study ate meat containing known amounts of MeIQx and PhIP, and urine collections were made 0-12 and 12-24 hr after a meal. MeIQx and PhIP were measured in urine after acid treatment that quantitatively hydrolyzes the Phase II conjugates to the respective parent amine. The extracts containing the HAAs were purified by immunoaffinity chromatography and analyzed by liquid chromatography using electrospray ionization-tandem mass spectrometry. The MeIQx content in the 0-12 hr urine increased after acid hydrolysis by a factor of 3-21-fold. After acid treatment, the total amount of MelQx (unmetabolized plus the N2-glucuronide and sulfamate metabolites) excreted in the 0-12 hr urine was 10.5 +/- 3.5% (mean +/- SD) of the dose, whereas the total amount of PhIP (unmetabolized plus acid-labile conjugate(s)) in the 0-12 hr period was 4.3 +/- 1.7% (mean +/- SD) of the dose. The total amount of PhIP in the 12-24 hr urine after acid treatment was 0.9 +/- 0.4% (mean +/- SD) of the dose. Linear regression analysis of the amounts of MeIQx and PhIP excreted in the 0-12 hr period expressed as a percentage of the ingested dose, for all subjects, gave a low but significant correlation (r = 0.37, P = 0.005). Linear regression analyses showed that lower total MeIQx (unmetabolized plus the N2-glucuronide and sulfamate metabolites) in urine was associated with higher CYP1A2 activity, whereas total PhIP (unmetabolized plus conjugated) in urine showed no association to CYP1A2 activity. These results indicate that in humans, MeIQx metabolism and disposition are more strongly influenced by CYP1A2 activity than are those of PhIP. Linear regression analysis found no association between NAT2 activity and the levels (unmetabolized plus acid-labile conjugates) of MeIQx or PhIP excreted in urine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 海关编码：
  2933990090
• 储存条件：
  库房应保持通风、低温和干燥的环境。

制备方法与用途

生物活性

PhIP 是一种在熟肉中形成的杂环芳香胺 (HAA)，可能具有致癌性。它能够破坏 DNA 并诱发基因突变，还表现出雌激素活性，这可能是其组织特异性致癌性的原因之一。

体外研究

PhIP 能广泛且主要地影响 miRNA 的表达模式。这种效应是通过激活雌激素受体α (ERα) 来实现的。由 PhIP 引发的 miRNA 不平衡可能成为乳腺癌中一种重要的非 DNA 损伤致癌机制。

体内研究

在 hCYP1A 小鼠模型中，PhIP 可诱导背侧前列腺叶的炎症、上皮细胞损伤以及前列腺上皮内瘤变，而对腹侧叶的影响较小。PhIP 还能够形成 DNA 加合物，并在啮齿类动物的前列腺中诱发氧化应激、腺泡萎缩和前列腺炎。

类别

有毒物品

可燃性危险特性

可燃；燃烧产生有毒氮氧化物烟雾

储运特性

库房通风，低温干燥

灭火剂

干粉、泡沫、砂土、二氧化碳，以及雾状水

反应信息

• 作为反应物：
  描述：

  2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶 在 溶剂黄146 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 3.5h， 以52%的产率得到1-甲基-2-硝基-6-苯基咪唑并[4,5-b]吡啶
  参考文献：
  名称：

  致癌物和诱变剂，PhIP，2-氨基-1-甲基-6-苯基-1 H-咪唑并[4,5- b ]吡啶的酯衍生物的合成和分解：异常的镍离子化学

  摘要：

  食物衍生的杂环胺（HCA）致癌物2-氨基-1-甲基-6-苯基-1 H-咪唑并[4,5- b ]吡啶PhIP通常在烤制过程中形成的HCA浓度最高炸肉和鱼。尽管它被认为是因接触HCA而导致人类癌症风险的重要因素，但是大概与DNA反应以引发癌变的PhIP代谢产物的化学作用仅引起了人们的粗略关注。我们合成了酯衍生物N-新戊氧基-2-氨基-1-甲基-6-苯基-1 H-咪唑并[4,5- b ]吡啶1b，并研究了其在水溶液中的化学性质。虽然1b由于太不稳定而无法分离，我们可以在-40°C的溶剂DMF- d 7中通过NMR方法对其进行表征。在水溶液中迅速分解，但其共轭酸1bH +，没有反应。的nitrenium离子，2，被困用N 3 -以形成异常的四唑加成物，16。在不存在N个3 - ，预期水化产物2未检测到，但还原产物，12，进行检测。虽然这样的产品通常作为三重态nitrenium离子的证据，高效捕集2乘N

  DOI：

  10.1021/jo070306p
• 作为产物：
  描述：

  3,5-二溴吡啶 在 镍 四(三苯基膦)钯 、 硫酸 、 氢气 、 硝酸 、 sodium carbonate 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 11.5h， 生成 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶
  参考文献：
  名称：

  Linstroem, Stefan; Eriksson, Mikael; Grivas, Spiros, Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812

  摘要：

  DOI：

文献信息

• XANTHINE DERIVATIVES, THEIR USE AS A MEDICAMENT, AND PHARMACEUTICAL PREPARATIONS COMPRISING THE SAME
  申请人：Max-Delbrück-Centrum für Molekulare Medizin

  公开号：EP3275885A1

  公开（公告）日：2018-01-31

  The invention relates to a xanthine derivative defined by chemical formula I or a salt thereof, its use as a medicament, especially for use in the treatment of serotonin-related diseases or disorders, and a pharmaceutical preparation comprising the xanthine derivative. The novel xanthine compounds are capable of inhibiting tryptophan hydroxylases (TPH) involved in the biosynthesis of serotonin and are effective in influencing the serotonin level in the body.

  本发明涉及一种由化学公式I定义的嘌呤衍生物或其盐，其用作药物，特别用于治疗与血清素相关的疾病或失调，以及包含该嘌呤衍生物的药物制剂。 这些新型的嘌呤化合物能够抑制参与血清素生物合成的色氨酸羟化酶（TPH），并且在影响体内的血清素水平方面有效。
• NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS
  申请人：ATOBE Masakazu

  公开号：US20100029690A1

  公开（公告）日：2010-02-04

  Nitrogen-containing heterocyclic compounds represented by the following Formula (1) are provided. The compounds or salts thereof have a strong EP1 antagonistic activity when they are administered to a human or an animal, and they are useful as an effective component of a pharmaceutical agent for prophylaxis and/or treatment of an overactive bladder, for example. Furthermore, they are useful as an effective component of a pharmaceutical agent for the prophylaxis and/or treatment of symptoms including frequent urination, urinary urgency and urinary incontinence.

  提供以下式（1）所代表的含氮杂环化合物。当这些化合物或其盐被给予人类或动物时，它们具有强烈的EP1拮抗活性，并且它们作为预防或治疗过度活动膀胱的药物的有效成分是有用的，例如。此外，它们作为预防或治疗包括频繁排尿、尿急和尿失禁等症状的药物的有效成分是有用的。
• BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS
  申请人：Atobe Masakazu

  公开号：US20100029733A1

  公开（公告）日：2010-02-04

  A nitrogen-containing bicyclic heterocyclic compound represented by the following formula (1) is provided. When the compound or a salt thereof is administered to a human being or an animal, the compound has a strong antagonistic action against EP1 receptors, and is useful, for example, as an active ingredient of a medicine for the prevention and/or treatment of overactive bladder. The compound is also useful as an active ingredient of a medicine for the prevention and/or treatment of symptoms such as frequency urinary, urinary urgency, or urinary incontinence.

  提供一种由以下式（1）表示的含氮双环杂环化合物。当该化合物或其盐被用于人类或动物时，该化合物对EP1受体具有强烈的拮抗作用，并且可用作预防和/或治疗膀胱过度活跃的药物的活性成分。该化合物还可用作预防和/或治疗频繁排尿、尿急或尿失禁等症状的药物的活性成分。
• Reactive Carbonyl-Scavenging Ability of 2-Aminoimidazoles: 2-Amino-1-methylbenzimidazole and 2-Amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine (PhIP)
  作者：Francisco J. Hidalgo、Esmeralda Alcón、Rosario Zamora

  DOI：10.1021/jf504320a

  日期：2014.12.10

  The carbonyl-scavenging ability of 2-amino-1-methylbenzimidazole (AMBI) and the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was investigated in an attempt to identify new routes that can modify the carbonyl content of foods. The reaction of both AMBI and PhIP with 2-alkenals, 2,4-alkadienals, 4-oxo-2-alkenals, 4,5-epoxy-2-alkenals, and 4-hydroxy-2-nonenal produced

  为了鉴定2-氨基-1-甲基苯并咪唑（AMBI）和杂环芳香胺2-氨基-1-甲基-6-苯基咪唑并[4,5- b ]吡啶（PhIP）的羰基清除能力，可以改变食品中羰基含量的新途径。AMBI和PhIP与2-烯醛，2,4-链二烯醛，4-氧代-2-烯醛，4,5-环氧-2-烯醛和4-羟基-2-壬烯的反应生成了荧光加合物，其结构确定了AMBI和2-戊烯之间产生的加合物。分离并通过一维和二维核磁共振和高分辨率质谱鉴定该加合物为2,10-二氢-2-乙基-10-甲基嘧啶[1,2- a ]苯并咪唑。这些加合物的形成与消除AMBI和PhIP平行。这PhIP与4-氧代-2-壬烯醛之间的反应E a为27.4kJ / mol。所有这些结果表明2-氨基咪唑可用于改变食品的羰基含量。同时，由于该反应使氨基化合物消失，因此可以使用脂质衍生的羰基化合物消除2-氨基咪唑，这为消除食品中的杂环芳香胺提供了新的策略。
• Synthesis and mutagenic potency of structural isomers of 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine
  作者：W. Chrisman、M. J. Tanga、M. G. Knize

  DOI：10.1002/jhet.5570450614

  日期：2008.11

  Synthesis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), three structural isomers, and two desphenyl PhIP congeners has been carried out. Mutagenic potency was evaluated using S. typhimurium strain TA98 in the Ames test. Mutagenic potency increased in relation to structural features in these heterocyclic amines that allow extended resonance between the phenyl and imidazo[4,5-b]pyridine

  已经进行了2-氨基-1-甲基-6-苯基咪唑并[4，5- b ]吡啶（PhIP），三个结构异构体和两个去苯基PhIP同类物的合成。使用鼠伤寒沙门氏菌菌株TA98在Ames试验中评估致突变力。与这些杂环胺中的结构特征相关的致突变力增加，从而允许苯基和咪唑并[4,5- b ]吡啶N 2-氨基取代基之间的共振延长。相比之下，PhIP异构体的取代不允许苯基参与其氨基咪唑共鸣杂合体，而去苯基同类物的诱变性比PhIP低86-234倍。