2006 Fiscal Year Final Research Report Summary
Control of intracellular signaling responsible for oxidative stress in blood cells
| Project/Area Number |
17590108
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
NUMAZAWA Satoshi Showa University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80180686)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Sachiko Showa University, School of Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (00197419)
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| Project Period (FY) |
2005 – 2006
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| Keywords | environment / signal transduction / oxidative stress / transcriptional regulation / drug response |
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| Research Abstract |
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.
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