Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Toxicology. 2013 Mar 8;305:30-40. doi: 10.1016/j.tox.2013.01.002. Epub 2013 Jan 11.
To investigate the protective effect of enzymatically modified isoquercitrin (EMIQ) on the hepatocarcinogenic process, we used a two-stage hepatocarcinogenesis model in N-diethylnitrosamine-initiated and thioacetamide (TAA)-promoted rats. We examined the modifying effect of co-administration with EMIQ on the liver tissue environment including hepatic macrophages and lymphocytes and on the induction mechanism of preneoplastic cell apoptosis during early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in randomly selected areas in liver sections. Co-administration with EMIQ suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) liver cells, as well as the number of CD3(+) lymphocytes. These effects were also suppressed by EMIQ. EMIQ increased liver levels of thiobarbituric acid-reactive substance and 8-hydroxydeoxyguanosine, and TUNEL(+) apoptotic cells, death receptor 5 (DR5)(+) cells and 4-hydroxy-2-nonenal(+) cells within GST-P(+) foci. Outside the GST-P(+) foci, EMIQ decreased the numbers of apoptotic cells and DR5(+) cells. These results suggest that TAA-induced tumor promotion involves activation of hepatic macrophages producing proinflammatory factors. EMIQ may suppress the TAA-induced tumor-promoting activity by an anti-inflammatory mechanism mediated by suppressing the activation of these macrophages. Furthermore, EMIQ may suppress tumor-promoting activity differentially between the inside and outside of GST-P(+) foci. Within GST-P(+) foci, EMIQ facilitates the apoptosis of preneoplastic cells through the upregulation of DR5. Outside the GST-P(+) foci, EMIQ suppresses apoptosis and the subsequent regeneration of non-transformed liver cells.
为了研究酶法改性异槲皮苷（EMIQ）对肝癌发生过程的保护作用，我们采用了二乙基亚硝胺（DEN）诱导和硫代乙酰胺（TAA）促进的大鼠两阶段肝癌发生模型。我们研究了 EMIQ 共同给药对肝组织环境（包括肝巨噬细胞和淋巴细胞）的修饰作用，以及在肝细胞肿瘤促进早期阶段对癌前细胞凋亡诱导机制的影响。TAA 增加了 GST-P（+）肝细胞灶的数量和面积，以及肝组织切片随机选择区域中增殖和凋亡细胞的数量。EMIQ 抑制了这些作用。TAA 还增加了 ED2（+）、环氧化酶-2（+）和血红素加氧酶-1（+）的肝细胞数量，以及 CD3（+）淋巴细胞的数量。这些作用也被 EMIQ 抑制。EMIQ 增加了肝脏中硫代巴比妥酸反应物质和 8-羟基脱氧鸟苷的水平，以及 GST-P（+）灶内 TUNEL（+）凋亡细胞、死亡受体 5（DR5）（+）细胞和 4-羟基-2-壬烯醛（+）细胞的数量。在 GST-P（+）灶外，EMIQ 减少了凋亡细胞和 DR5（+）细胞的数量。这些结果表明，TAA 诱导的肿瘤促进涉及激活产生促炎因子的肝巨噬细胞。EMIQ 可能通过抑制这些巨噬细胞的激活来抑制炎症机制，从而抑制 TAA 诱导的肿瘤促进活性。此外，EMIQ 可能在 GST-P（+）灶内外以不同的方式抑制肿瘤促进活性。在 GST-P（+）灶内，EMIQ 通过上调 DR5 促进癌前细胞凋亡。在 GST-P（+）灶外，EMIQ 抑制凋亡和随后非转化肝细胞的再生。
