2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Is Selectively Toxic to Primary Dopaminergic Neurons In Vitro
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Is Selectively Toxic to Primary Dopaminergic Neurons In Vitro
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DOI：
10.1093/toxsci/kfu060
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发表时间：
2014-07-01
影响因子：
3.8
通讯作者：
Cannon, Jason R.
中科院分区：
文献类型：
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作者：
Griggs, Amy M.;Agim, Zeynep S.;Cannon, Jason R.
帕金森病(PD)是第二常见的神经退行性疾病。许多资料表明帕金森病的病因与多种环境因素有关。大多数病例被认为是遗传易感性和环境因素共同作用的结果。长期接触饮食因素，包括肉类，已被确定为潜在的风险因素。虽然已知高温肉类烹饪过程中产生的杂环胺具有致癌性，但其对神经系统的影响尚未深入研究。在这项研究中，我们在体外研究了2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）的神经毒性作用，PhIP是一种在熟肉中含量很高的杂环胺。我们使用大鼠胚胎中脑原代培养物测试了PhIP和两种主要的I期代谢物N-OH-PhIP和4'-OH-PhIP的毒性。这种培养系统包含多巴胺能和非多巴胺能神经元，这使得神经毒性的特异性很容易检查。我们发现暴露于PhIP或N-OH-PhIP对原代培养的多巴胺能神经元有选择性毒性，导致多巴胺能神经元百分比下降。存活的多巴胺能神经元的神经突长度减少。暴露于4'-OH-PhIP没有产生显著的神经毒性。PhIP还增加了多巴胺能神经元中氧化损伤标志物4-羟基-2-壬烯醛（HNE）和3-硝基酪氨酸的形成。n -乙酰半胱氨酸预处理具有保护作用。最后，用蓝莓提取物（一种已知具有抗氧化和其他保护机制的膳食因子）处理，可以防止phip引起的毒性。总的来说，我们的研究首次表明，PhIP可能通过诱导氧化应激对多巴胺能神经元具有选择性毒性。
Parkinson's disease (PD) is the second most common neurodegenerative disease. Much data has linked the etiology of PD to a variety of environmental factors. The majority of cases are thought to arise from a combination of genetic susceptibility and environmental factors. Chronic exposures to dietary factors, including meat, have been identified as potential risk factors. Although heterocyclic amines that are produced during high-temperature meat cooking are known to be carcinogenic, their effect on the nervous system has yet to be studied in depth. In this study, we investigated neurotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a highly abundant heterocyclic amine in cooked meat, in vitro. We tested toxicity of PhIP and the two major phase I metabolites, N-OH-PhIP and 4'-OH-PhIP, using primary mesencephalic cultures from rat embryos. This culture system contains both dopaminergic and nondopaminergic neurons, which allows specificity of neurotoxicity to be readily examined. We find that exposure to PhIP or N-OH-PhIP is selectively toxic to dopaminergic neurons in primary cultures, resulting in a decreased percentage of dopaminergic neurons. Neurite length is decreased in surviving dopaminergic neurons. Exposure to 4'-OH-PhIP did not produce significant neurotoxicity. PhIP treatment also increased formation of oxidative damage markers, 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine in dopaminergic neurons. Pretreatment with N-acetylcysteine was protective. Finally, treatment with blueberry extract, a dietary factor with known antioxidant and other protective mechanisms, prevented PhIP-induced toxicity. Collectively, our study suggests, for the first time, that PhIP is selectively toxic to dopaminergic neurons likely through inducing oxidative stress.