Control of intracellular signaling responsible for oxidative stress in blood cells

众所周知，骨髓细胞易受外源性氧化应激的影响。然而，控制血细胞易感性的分子机制尚不清楚。本研究的目的是证明应激蛋白的作用是否参与骨髓源性细胞对氧化应激的易感性。毒性苯代谢物，如对苯二酚和苯醌，在几种白血病细胞系（血细胞祖细胞模型）和小鼠骨髓细胞中，与非血细胞（如HepG2肝癌和WI-38成纤维细胞）相比，在显著较低浓度下诱导细胞死亡。这些氧化剂在血细胞中诱导血红素加氧酶-1 （H0-1）和NAD(P) h -醌氧化还原酶1 (NAD(P) h -醌氧化还原酶1)，这是典型的应激蛋白，可减轻应激诱导的细胞损伤，但其程度远低于非血细胞。Nrf2（一种在应激蛋白基因表达中起核心作用的转录因子）的功能以及靶顺式调节元件抗氧化反应元件（ARE）的反应在血细胞模型中受损。这些结果表明，血细胞对苯代谢物的易感性部分是由于Nrf2-ARE信号受损引起的应激蛋白反应受限。我们进一步研究了氧化应激是否参与5-氟尿嘧啶（5-FU）介导的骨髓毒性。5-FU在体内和体外均能提高骨髓细胞HO-1蛋白水平。5-FU刺激骨髓细胞中活性氧的产生。此外，5- fu介导的HO-1诱导和髓毒性是平行发生的。这些结果提示氧化应激在一定程度上参与了5-FU引起的骨髓毒性。

It has been well known that bone marrow cells are susceptible to xenobiotic-induced oxidative stress. However, molecular mechanisms that governed susceptibility of blood cells are poorly understood. Aim of the present study was to demonstrate whether responsibilities of the stress proteins are involved in the susceptibility to oxidative stress in bone marrow derived cells.Toxic benzene metabolites, such as hydroquinone and benzoquinone, induced cell death at significantly lower concentrations in several leukemia cell lines, a model of blood cell progenitors as well as mouse bone marrow cells as compared to non-blood cells, such as HepG2 hepatoma and WI-38 fibroblast cells. These oxidants induced heme oxygenase-1 (H0-1) and NAD(P)H-quinone oxidoreductase 1, typical stress proteins which diminish stress-induced cell damage, in the blood cells but to a far lesser extent than in the non-blood cells. Functions of Nrf2, a transcription factor that bares a central role in gene expressions of the stress proteins, and responses of the target cis-regulatory element, antioxidant responsive element (ARE), were impaired in the blood cell models. These results suggest that susceptibility of blood cells to benzene metabolites is partly due to the restricted response of the stress proteins caused by the impaired Nrf2-ARE signaling.We have further examined whether oxidative stress is involved in 5-fluorouracil (5-FU)-mediated myelotoxicity. 5-FU increased HO-1 protein in bone marrow cells in vitro as well as in vivo. 5-FU stimulated production of reactive oxygen species in bone marrow cells. Furthermore, 5-FU-mediated HO-1 induction and myelotoxicity occurred in a parallel fashion. These results suggest that oxidative stress is partly involved in myelotoxicity caused by 5-FU.