1994 Fiscal Year Final Research Report Summary
Multiple Oxidative Stress Responses for Hepatic Glutathione Depletion Evoked by Drugs and chemicals
| Project/Area Number |
05671843
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
YOSHIDA Takemi Sch.Pharmaceut.Sci., Showa University Professor, 薬学部, 教授 (20138415)
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| Co-Investigator(Kenkyū-buntansha) |
OGURO Takiko Showa university Assistant Professor, 薬学部, 助手 (10185572)
TANAKA Sachiko Showa university Assistant Professor, 薬学部, 助手 (00197419)
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| Project Period (FY) |
1993 – 1994
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| Keywords | Glutathione depletion / oxidative stress / Metallothionein / Heme oxygenase / Cytochrome P450 / HepG2 cell / Phorone / Dipyridyls |
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| Research Abstract |
The experimental results of this project were as follows. Many drugs and chemicals were found to produce the decrease in hepatic glutathione (GSH) content and the inverse induction of metallothionein (MT) and heme oxygenase (HO) synthesis in rats. The induction of MT and HO by trans- and cis-stilbene oxide (TSO and CSO), and by phorone was preceded by the large increases in MT-1 and HO-1 mRNAs, respectively. In vitro cultured HepG2 cells expressed largely HO-1 mRNA when exposed to TSO and phorone in a concentration-dependent manner, supporting the finding observed in vivo. However, CSO failed to increase HO-1 mRNA.The increased expression of HO-1 mRNA in HepG2 cells by TSO and phorone was inhibited by the presence of a singlet oxygen scavenger DABCO,but not by tocopherol.
Many dipyridyl compounds produced differential effects on GSH content, hepatic P450s and HO activity. Of the compounds, 2,2'-dipyridyl (DP) had almost similar effects to that seen in TSO and phorone. DP and phorone caused the transient depletion of cytosolic, mitochondrial and nuclear GSH content, and the increases in HO-1 and c-jun mRNAs.
In relation to this experimental project, many pyridine and imidazole-containing compounds were found to produce differentially the induction of P450s. Of the compounds, 1-benzylimidazole produce the induction of P450 2B1/2 testosterone-dependently.
Throughout this experimental project, we revealed that GSH depletion evoked by drugs and chemicals could lead to the increased expression of various mRNAs of oxidative stress responsible enzymes and proteins.
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