Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
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DOI：
10.1016/s0027-5107(02)00155-0
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发表时间：
2002-09-30
影响因子：
2.3
通讯作者：
Creton, S
中科院分区：
文献类型：
--
作者：
Gooderham, NJ;Zhu, H;Creton, S
含有肉类的食物经烹煮后会形成杂环胺2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP），可诱发大鼠的结肠癌、前列腺癌和乳腺癌，这些肿瘤与西方饮食密切相关。在食用肉类后，PhIP被迅速吸收，代谢和生物活化为DNA破坏物种。因此，PhIP应被视为人类癌症的候选病原体。在模型哺乳动物细胞培养系统中进行的体外研究和在转基因动物体内进行的研究表明，PhIP诱导的突变具有剂量依赖性，并描述了该化学品特有的突变“指纹”。这种遗传毒性依赖于CYP 1家族代谢活化，在μ M浓度下可在这些模型系统中检测到。在早期时间点，PhIP处理的细胞显示出导致生长和循环改变的毒性的细微迹象。使用共培养系统，其中一个细胞系生物激活PhIP与第二个细胞系作为目标，我们表明，在人类淋巴母细胞样靶细胞，PhIP诱导的剂量和时间依赖性的S期延迟的细胞周期。随着时间的推移，细胞群体变得越来越凋亡，剩余的幸存者携带突变的基因集。经处理的细胞的转录谱表明参与细胞周期调节、应激反应、受体和肿瘤相关基因的基因的差异表达。显著的是p21（cip 1/waf 1）转录物的升高，并且Western印迹分析证实了p21（cip 1/waf 1）和p53蛋白的诱导。这些变化的剂量依赖性和时间方面表明，响应于PhIP的细胞周期和生长的操纵是突变体选择的前体。减少PhIP剂量允许解剖有利于细胞生长而不是抑制的不同细胞反应电池。这种促生长刺激是雌激素样的，包括改变基因表达、增殖和细胞行为。在人乳腺细胞系中，这些PhIP介导的促雌激素反应被抗雌激素ICI 182，780抑制。PhIP在细胞中诱导的这种分子和遗传反应范围是相当显著的。它能够激活S期细胞周期检查点，改变基因表达导致细胞凋亡和突变频率增加可能是其遗传毒性的直接后果。相反，其促雌激素活性可能是克隆扩张的驱动力。我们认为，这些PhIP诱导的基因组和细胞事件设法操纵细胞周期和生存。了解这些分子过程以及化学品的遗传毒理学将有助于确定PhIP参与致癌作用，并揭示其组织特异性。(C)2002 Elsevier Science B. V.保留所有权利。
The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed when meat containing food is cooked, induces cancer of the colon, prostate and mammary gland of rats, tumours that are strongly associated with a Western diet. After consumption of a meat meal, PhIP is rapidly absorbed, metabolised and bioactivated to DNA damaging species. Thus, PhIP should be considered as a candidate etiological agent for human cancer. Studies in vitro in model mammalian cell culture systems, and in vivo in transgenic animals, have shown that mutation induced by PhIP is dose dependent and describes a mutational "fingerprint" that is characteristic of the chemical. This genetic toxicity is dependent upon CYP1 family metabolic activation and is detectable in these model systems at muM concentrations. At early time points, PhIP treated cells show subtle signs of toxicity that lead to altered growth and cycling. Using co-culture systems where one cell line bioactivates PhIP with a second cell line as target, we showed in human lymphoblastoid target cells that PhIP induced a dose- and time-dependent S-phase delay of the cell cycle. With time, the cell population became increasingly apoptotic with remaining survivors carrying a mutated gene set. Transcript profiling of treated cells indicated differential expression of genes involved in cell cycle regulation, stress response, receptors and tumour related genes. Prominent was elevation of p21(cip1/waf1) transcript and Western blot analysis confirmed induction of p21(cip1/waf1) and p53 proteins. The dose dependency and temporal aspects of these changes indicate that manipulation of the cell cycle and growth in response to PhIP is a precursor to mutant selection. Reduction of the PhIP dose allows dissection of a different battery of cellular responses that favour cell growth rather than inhibition. This pro-growth stimulus is oestrogen-like and encompasses altered gene expression, proliferation and cell behaviour. In human breast cell lines, these PhIP-mediated pro-oestrogenic responses are inhibited by the anti-oestrogen ICI 182,780. This range of molecular and genetic responses induced in cells by PhIP is quite remarkable. Its ability to activate S-phase cell cycle checkpoint, alter gene expression leading to apoptosis and an increased frequency of mutation are probably direct consequences of its genetic toxicity. In contrast, its pro-oestrogenic activity is likely to be a driver of clonal expansion. We suggest that these PhIP-induced genomic and cellular events contrive to manipulate cell cycle and survival. Understanding these molecular processes as well as the genetic toxicology of the chemical will help to define the involvement of PhIP in carcinogenesis and shed light upon its tissue specificity. (C) 2002 Elsevier Science B.V. All rights reserved.