Bendadani Carolin, Meinl Walter, Monien Bernhard H, Dobbernack Gisela, Glatt Hansruedi
Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
Arch Toxicol. 2014 Mar;88(3):815-21. doi: 10.1007/s00204-013-1182-6. Epub 2013 Dec 13.
The common polycyclic aromatic hydrocarbon 1-methylpyrene is hepatocarcinogenic in the newborn mouse assay. In vitro studies showed that it is metabolically activated via benzylic hydroxylation and sulphation to a reactive ester, which forms benzylic DNA adducts, N(2)-(1-methylpyrenyl)-2'-deoxyguanosine (MPdG) and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine (MPdA). Formation of these adducts was also observed in animals treated with the metabolites, 1-hydroxymethylpyrene and 1-sulphooxymethylpyrene (1-SMP), whereas corresponding data are missing for 1-methylpyrene. In the present study, we treated mice with 1-methylpyrene and subsequently analysed blood serum for the presence of the reactive metabolite 1-SMP and tissue DNA for the presence of MPdG and MPdA adducts. We used wild-type mice and a mouse line transgenic for human sulphotransferases (SULT) 1A1 and 1A2, males and females. All analyses were conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry, for the adducts with isotope-labelled internal standards. 1-SMP was detected in all treated animals. Its serum level was higher in transgenic mice than in the wild-type (p < 0.001). Likewise, both adducts were detected in liver, kidney and lung DNA of all exposed animals. The transgene significantly enhanced the level of each adduct in each tissue of both sexes (p < 0.01-0.001). Adduct levels were highest in the liver, the target tissue of carcinogenesis, in each animal model used. MPdG and MPdA adducts were also observed in rats treated with 1-methylpyrene. Our findings corroborate the hypothesis that 1-SMP is indeed the ultimate carcinogen of 1-methylpyrene and that human SULT are able to mediate the terminal activation in vivo.
常见的多环芳烃1-甲基芘在新生小鼠实验中具有肝致癌性。体外研究表明，它通过苄基羟基化和硫酸化代谢活化成一种反应性酯，该酯会形成苄基DNA加合物，即N(2)-(1-甲基芘基)-2'-脱氧鸟苷(MPdG)和N(6)-(1-甲基芘基)-2'-脱氧腺苷(MPdA)。在用代谢物1-羟甲基芘和1-磺氧基甲基芘(1-SMP)处理的动物中也观察到了这些加合物的形成，而关于1-甲基芘的相应数据则缺失。在本研究中，我们用1-甲基芘处理小鼠，随后分析血清中反应性代谢物1-SMP的存在情况，并分析组织DNA中MPdG和MPdA加合物的存在情况。我们使用了野生型小鼠以及转染了人类磺基转移酶(SULT)1A1和1A2的小鼠品系，包括雄性和雌性。所有分析均使用超高效液相色谱-串联质谱法，并使用同位素标记的内标物进行加合物分析。在所有处理过的动物中均检测到了1-SMP。其血清水平在转基因小鼠中高于野生型小鼠(p < 0.001)。同样，在所有暴露动物的肝脏、肾脏和肺DNA中均检测到了这两种加合物。转基因显著提高了两性各组织中每种加合物的水平(p < 0.01 - 0.001)。在所使用的每种动物模型中，加合物水平在致癌作用的靶组织肝脏中最高。在用1-甲基芘处理的大鼠中也观察到了MPdG和MPdA加合物。我们的研究结果证实了以下假设：1-SMP确实是1-甲基芘的最终致癌物，并且人类SULT能够在体内介导终末活化。
