|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1992 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1991 : ¥1,000,000 (Direct Cost : ¥1,000,000)
The experimental results of this project are as follows.
Azathiopurine (2mmol/kg), an immunodepressor, was found to be an inducer of home oxygenase (HO) after depleting hepatic glutathione (GSH) content. Allopurinol-pretreatment inhibited azathiopurine-mediated induction of HO. Western blot analysis revealed that trans- and cis-stilbene oxide (TSO and CSO) decreased constitutive cytochrome P-450 species, 2C11 and 2E1, accompanying by HO induction. TSO and CSO, however, significantly induced P-450 2B. Repeated administration of TSO or CSO at 0.5mmol/kg produced the induction of P-450 2B, 2C11, 2E1, 2C6 and 3A2 ; however, at 2mmol/kg, they did not induce these P-450 species except 2B. As described above, TSO and CSO induced P-450 2B and altered constitutive P-450 content in a dose-dependent manner. Additionally, TSO and CSO produced the induction of hepatic metallothionein (MT), together with the increase of zinc content. after decreasing GSH content. The aforementioned various actions of TSO and CSO, together with MT induction, were not affected by pretreatment with various radical scavengers. However, pretreatment with perfluorodecanoic acid significantly inhibited TSO- and CSO-mediated changes in the liver, but further studies are required to clarify this inhibitory mechanism. Possible changes in GSH distribution, -SH and -S-S- exchange, after TSO and CSO administration remains to be elucidated. In addition, preparation of HO antibody and mechanistic action of TSO and CSO at transcriptional step also remains to be further study. In relation to this project, we also found that some pyridine derivatives were to be HO inducers. Throughout this project, we revealed various supportive findings indicating that GSH depletion could lead to the induction of various stress-responsible enzymes and protein.