| Co-Investigator(Kenkyū-buntansha) |
SAI Kimie National Institute of Health Sciences Div.of Cellular and Molecular Toxicology S, 毒性部, 主任研究官 (20195960)
HASEGAWA Ryuichi National Institute of Health Sciences Div.of Risk Assesment chair of Division, 室長 (50112496)
KANNO Jun National Institute of Health Sciences Div.of Cellular and Molecular Toxicology S, 毒性部, 室長 (90186172)
TROSKO James E. Michigan State University Dept.of Periatrics & Human Development Professor, 小児科学・人類発生学部, 教授
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| Research Abstract |
This research aimes to investigate possible interaction and co-ordination among the oxidative DNA damage, an induction of apoptosis, and the gap junctional intercellular communication (GJIC), which seems to be the mechanism of promoting action in the murine hepatocarcinogenesis by pentachlorophenol (PCP). P53-null mice were applied in this research, because of its following characteristics ; 1)accumulation of DNA damages, 2)inhibition of apoptosis and 3)inhibition of GJIC.
Results obtained are as follows : 1)In the study using p53-deficient mouse, there was neither enhancement of oxidative DNA damage nor accelerated cell proliferation in the liver of p53-deficient mouse after treatment with PCP in diet for 2 weeks, showing no clear evidence of involvement of p53 to suppress the tumor-promoting action by PeP.2) In vitro study using hepatic epithelial cell line (WB cell) demonstrated the bi-phasic inhibitory effects of PCP on GJIC in WB cells. PCP also inhibited apoptosis induced in v-myc-transfected WB cells, accompanying an inhibition of GJIC.Inhibition of GJICon WB cell at the first-phase was correlated with the activation of mitogen activated protein kinase which is activated by oxidative stress, and the second inhibition was up-regulated by antioxidant, epigallocatechin gallate. 3) Our method of in vivo GJIC-analysis showed the inhibition of GJIC in the mouse hepatic tissue after treatment with PCP, supporting our previous in vitro findings.
Theses studies demonstrated that PCP inhibited both GJIC and apoptosis, showing a possible involvement of oxidative stress in both phenomena, and suggest significant interaction of those biological events in tumor-promoting activity in POP, although the role of suppression in p53 along with theses events was not proven in the present research.
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