Inoue Kaoru, Yoshida Midori, Takahashi Miwa, Fujimoto Hitoshi, Ohnishi Kuniyoshi, Nakashima Koichi, Shibutani Makoto, Hirose Masao, Nishikawa Akiyoshi
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Food Chem Toxicol. 2009 Apr;47(4):752-9. doi: 10.1016/j.fct.2009.01.003. Epub 2009 Jan 8.
Madder color (MC) has been shown to exert carcinogenic potential in the rat kidney in association with degeneration, karyomegaly, increased cell proliferation of renal tubule cells and increased renal 8-OHdG levels. To clarify the causal relationship of components and metabolites of MC to renal carcinogenesis, male F344 rats were fed lucidin-3-O-primeveroside (LuP) or alizarin (Alz), and the genotoxic LuP metabolites lucidin (Luc) or rubiadin (Rub) for up to 26 weeks. After one week and four weeks, Luc did not induce any renal changes. In contrast, after one week, cortical tubule degeneration was apparent in the Alz and LuP groups, and cytoplasmic swelling with basophilic change and karyomegaly in the outer medulla was observed only in the Rub group. LuP and Rub increased the proliferative activity of tubule cells in the outer medulla, and Alz and LuP increased renal 8-OHdG levels. After 26 weeks, Rub but not Alz induced atypical tubules, a putative preneoplastic lesion, and karyomegaly in the outer medulla. These results indicate that Rub may be a potent carcinogenic metabolite of MC, targeting proximal tubule cells in the outer medulla, although oxidative stress increased by Alz or LuP might also be involved in renal carcinogenesis by MC.
已证实茜草色素（MC）在大鼠肾脏中具有致癌潜力，与变性、核肿大、肾小管细胞增殖增加以及肾脏8-羟基脱氧鸟苷（8-OHdG）水平升高有关。为了阐明MC的成分和代谢产物与肾脏致癌作用之间的因果关系，给雄性F344大鼠喂食鲁比定-3-O-樱草糖苷（LuP）或茜素（Alz），以及具有遗传毒性的LuP代谢产物鲁比定（Luc）或玉红苷（Rub），持续26周。在1周和4周后，Luc未引起任何肾脏变化。相比之下，1周后，Alz组和LuP组出现皮质小管变性，仅在Rub组观察到外髓质细胞质肿胀伴嗜碱性改变和核肿大。LuP和Rub增加了外髓质小管细胞的增殖活性，Alz和LuP增加了肾脏8-OHdG水平。26周后，Rub而非Alz诱导了非典型小管，这是一种假定的癌前病变，以及外髓质中的核肿大。这些结果表明，Rub可能是MC的一种强效致癌代谢产物，以外髓质近端小管细胞为靶点，尽管Alz或LuP增加的氧化应激也可能参与MC的肾脏致癌作用。
