PDF(Pubmed)
Abstract：
We previously found that feeding rats with broccoli or cauliflower leads to the formation of characteristic DNA adducts in the liver, intestine and various other tissues. We identified the critical substances in the plants as 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate and its degradation product 1-MIM-OH. DNA adduct formation and the mutagenicity of 1-MIM-OH in cell models were drastically enhanced when human sulfotransferase (SULT) 1A1 was expressed. The aim of this study was to clarify the role of SULT1A1 in DNA adduct formation by 1-MIM-OH in mouse tissues in vivo. Furthermore, we compared the endogenous mouse Sult1a1 and transgenic human SULT1A1 in the activation of 1-MIM-OH using genetically modified mouse strains. We orally treated male wild-type (wt) and Sult1a1-knockout (ko) mice, as well as corresponding lines carrying the human SULT1A1-SULT1A2 gene cluster (tg and ko-tg), with 1-MIM-OH. N2-(1-MIM)-dG and N6-(1-MIM)-dA adducts in DNA were analysed using isotope-dilution UPLC-MS/MS. In the liver, caecum and colon adducts were abundant in mice expressing mouse and/or human SULT1A1, but were drastically reduced in ko mice (1.2-10.6% of wt). In the kidney and small intestine, adduct levels were high in mice carrying human SULT1A1-SULT1A2 genes, but low in wt and ko mice (1.8-6.3% of tg-ko). In bone marrow, adduct levels were very low, independently of the SULT1A1 status. In the stomach, they were high in all four lines. Thus, adduct formation was primarily controlled by SULT1A1 in five out of seven tissues studied, with a strong impact of differences in the tissue distribution of mouse and human SULT1A1. The behaviour of 1-MIM-OH in these models (levels and tissue distribution of DNA adducts; impact of SULTs) was similar to that of methyleugenol, classified as \"probably carcinogenic to humans\". Thus, there is a need to test 1-MIM-OH for carcinogenicity in animal models and to study its adduct formation in humans consuming brassicaceous foodstuff.
摘要：
我们以前发现，用西兰花或花椰菜喂养大鼠会导致肝脏中特征性DNA加合物的形成，肠和各种其他组织。我们确定了植物中的关键物质为1-甲氧基-3-吲哚基甲基（1-MIM）芥子油苷及其降解产物1-MIM-OH。当表达人磺基转移酶（SULT）1A1时，细胞模型中1-MIM-OH的DNA加合物形成和诱变性大大提高。这项研究的目的是阐明SULT1A1在小鼠组织中1-MIM-OH形成DNA加合物中的作用。此外，我们使用转基因小鼠品系比较了内源性小鼠Sult1a1和转基因人SULT1A1在1-MIM-OH激活中的作用。我们口服处理雄性野生型（wt）和Sult1a1敲除（ko）小鼠，以及携带人类SULT1A1-SULT1A2基因簇（tg和ko-tg）的相应品系，1-MIM-OH使用同位素稀释UPLC-MS/MS分析DNA中的N2-（1-MIM）-dG和N6-（1-MIM）-dA加合物。在肝脏中，盲肠和结肠加合物在表达小鼠和/或人SULT1A1的小鼠中丰富，但在ko小鼠中急剧减少（重量的1.2-10.6％）。在肾脏和小肠中，在携带人SULT1A1-SULT1A2基因的小鼠中，加合物水平很高，但wt和ko小鼠的含量较低(tg-ko的1.8-6.3%)。在骨髓中，加合物水平非常低，独立于SULT1A1状态。在胃里，他们四行都很高。因此，在所研究的七个组织中，有五个主要由SULT1A1控制加合物的形成，小鼠和人SULT1A1的组织分布差异具有很强的影响。1-MIM-OH在这些模型中的行为（DNA加合物的水平和组织分布；SULTs的影响）与甲基丁香酚相似，归类为“可能对人类致癌”。因此，有必要在动物模型中测试1-MIM-OH的致癌性，并研究其在人类食用黄铜食品中的加合物形成。
