Novel effects and mechanisms of action of heme and soy isoflavones

血红素是一种广泛用于补充铁的食品化学品。作为血红蛋白和许多其他血色素蛋白的修复基，血红素是人体必需的分子。过量的游离血红素是一种促氧化剂和有毒物质，被血红素加氧酶(HO)降解为铁、一氧化碳和胆绿素，后者迅速转化为抗氧化剂胆红素。HO有两种同工酶，即诱导型HO-1和组成型HO-2。HO-1的诱导是对抗氧化应激的重要防御机制，一些HO抑制剂具有抗肿瘤活性。在这个项目中，我利用不同类型的人体细胞，评估和分析了食物化学物质如血红素铁和大豆异黄酮对血红素分解代谢的影响和作用机制。长期的低氧降低了HO-2和HO-1的表达水平，这些HOS的下调是在转录和转录后水平上引起的。SiRNA下调110-2可诱导HO-1表达，而HO-2在一定条件下下调HO-1可增加细胞内血红素含量，提示HO-2在维持细胞内血红素水平和调控HO-1表达中具有重要意义。大豆异黄酮染料木素抑制了血红素和其他化学物质对HO-1的诱导，而另一种大豆异黄酮大豆苷元在某些情况下不抑制HO-1的诱导。结合我们的其他实验结果，这些异黄酮类化合物对HO-1诱导的抑制作用可能是通过雌激素受体非依赖性机制实现的。

Heme is widely used as a food chemical for iron supplementation. Heme is an essential molecule for us as prosthetic groups for hemoglobin and many other hemoproteins. Excess free heme is a pro-oxidant and toxic, and is degraded by heme oxygenase (HO) to iron, CO and biliverdin, which is rapidly converted to bilirubin, an antroxidant. There are two isozymes of HO, namely inducible HO-1 and constitutive 110-2. Induction of HO-1 is an important defense mechanism against oxidative stress, and some HO inhibitors have antitumor activity. In this project, I have been evalutated the effects and analyzed the mechanisms of action of food chemicals such as heme iron and soy isoflavones on heme catabolism, using various types of human cells.Prolonged hypoxia decreased the expression level of HO-2 as well as that of HO-1, and these down-regulations of HOs were caused at both transcriptional and post-transcriptional levels. Down-regulation of 110-2 by siRNA induced the HO-1 expression, and HO-2 knock-down 1 under some conditions increased the intracellular heme content, suggesting the significance of HO-2 in the maintenance of cellular heme levels and in the regulation of HO-1 expression. Genistein, a soy isoflavone, inhibited the induction of HO-1 by heme and other chemicals, while daidzein, another soy isoflavone, did not inhibited the induction of HO-1 in some cases. Together with results of our other experiments, these inhibitory effects of isoflavones on HO-1 induction were suggested to be mediated by estrogen receptor-independent mechanism.