Interaction between metabolism and transport of toxicological-relevant substances in the gastrointestinal barrier

多环芳烃（PAH）是一大类普遍存在的环境污染物，其中致癌物苯并[a]芘（BP）是研究得最好的代表。非吸烟者摄取多环芳烃的主要来源是日常饮食。多环芳烃只有在加工（加热和干燥）和制备（例如烟熏和烧烤）肉类、鱼类和植物油和脂肪等高脂肪食品时才会大量形成。在本项目的第一阶段，我们在转运蛋白敲除小鼠中研究了BP的解毒和肝胆排泄，研究了两种abc转运蛋白乳腺癌耐药蛋白（Bcrp/Abcg2）和多药耐药相关蛋白2 （Mrp2/Abcc2）的缺乏。数据显示，这两种转运蛋白在BP从体内排泄中起重要作用。此外，我们可以在体内研究中表明，一种食物成分，主要的类黄酮槲皮素，强烈地增加了体内BP的肝胆排泄。然而，在现实中，人类单独暴露于BP的情况从未发生过：多环芳烃的混合物总是通过营养吸收。这些混合物部分由致癌性化合物如BP组成，但按百分比计算，非致癌性多环芳烃如芘和氟蒽的比例很大。然而，这种非致癌性和致癌性多环芳烃混合物对分子机制的影响仍未得到充分的研究和了解。因此，本项目拟在上一期资助成果的基础上，进一步研究此类真实多环芳烃混合物对BP代谢、受体活性和遗传毒性的影响。重要的终点包括通过检测参与生物激活或解毒的特征代谢物（DNA加合物，代谢物谱分析），诱导与代谢相关的基因表达和核受体途径来改变BP代谢的变化，最后，使用人源化受体小鼠模型对体外数据进行体内验证。该项目的结果有望有助于更好地理解人类真实多环芳烃暴露的分子效应，而不是经常被明确描述的单一暴露，从而更好地评估BP的致癌潜力和对人类的相关风险。

Polycyclic aromatic hydrocarbons (PAH) comprise a large group of ubiquitously occurring environmental contaminants with the pro-carcinogen benzo[a]pyrene (BP) as best studied representative. The main source of PAH uptake for non-smokers is the daily diet. PAH are only formed in significant amounts during processing (heating and drying) and preparation (e.g. smoking and grilling) of fatty foods such as meat, fish and vegetable oils and fats. In the first period of this project BP its detoxication and hepatobiliary excretion was studied in transporter knockout mice investigating the lack of the two ABC-transporters Breast Cancer Resistance Protein (Bcrp/Abcg2) and Multidrug Resistance-associated Protein 2 (Mrp2/Abcc2). The data showed an important role of these two transporters for BP excretion from the body. Additionally we could show in an in vivo study that a food component, the prominent flavonoid Quercetin, strongly increases the hepatobiliary excretion of BP from the body.However, in reality a mono-exposure of humans with BP alone never occurs: always mixtures of PAH are taken up by nutrition. These mixtures consist partly of carcinogenic compounds such as BP, but in percentage terms in substantial proportions of non-carcinogenic PAH such as pyrene and fluoranthene. However, the influence of such mixtures of non-carcinogenic and carcinogenic PAHs on the molecular mechanisms is still inadequately investigated and understood. Accordingly, this project is aimed to investigate the impact of such real PAH mixtures on the metabolism, receptor activity and the genotoxicity of BP based on the results of the last funding period. Important endpoints comprise changes of the metabolism of BP by detection of characteristic metabolites involved in bioactivation or detoxification (DNA adducts, analysis of metabolite profile), the induction of gene expression and nuclear receptor pathways associated with the metabolism and finally, the in vivo verification of the in vitro data using humanized receptor mouse models.The results of this project are expected to contribute to a better understanding of molecular effects of real human PAH exposure in contrast to the often well-characterized single exposure and in turn allowing a better assessment of the carcinogenic potential of BP and the associated risk to humans.