Correlation of Increased Mortality with the Suppression of Radiation-inducible Microsomal Epoxide Hyderolase and Glutathione S-Transferase Gene Expression by Dexamethasone : Effects on Vitalmin C and E-Induced Radioprotection

다국어 초록 (Multilingual Abstract)

Previous studies in this laboratory have shown that γ-ray ionizing radiation in combination with oltipraz, a radioprotective agent, enhances hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) expression. The present study was designed to investigate the effects of dexamethasone on the radiation inducible expression of mEH and rGST genes and on the vitamin C and E-induced radioprotective effects in association with the expression of the genes. Treatment of rats with a single dose of dexamethasone(0.01-1 ㎎/㎏, p.o.) caused a dose dependent decrease in the constitutive mEH gene expression at 24 hr. The radiation-inducible mEH mRNA level (threefold increase after 3 Gy γ irradiation) was decreased by 21％ and 88％ by dexamethasone at the doses of 0.1 and 1 ㎎/㎏, respectively. Although dexamethasone alone caused 2 to 5 fold increases in the hepatic rGSTA2 mRNA level, rats treated with dexamethasone prior to 3 Gy irradiation exhibited 80％-93％ suppression in the radiation inducible increases in the rGSTA2 mRNA level. The inducible rGSTA3 and rGSTA5 mRNA levels were also significantly decreased by dexamethasone, whereas the rGSTM1 mRNA level was reduced to a lesser extent. Vitamin C and/or E, however, failed to enhance the radiation-inducible increases in hepatic mEH and rGST mRNA levels. Whereas rats exposed to 3 Gy irradiation with or without vitamin C treatment (30 or 200 ㎎/㎏/day, p.o., 2 days) exhibited∼threefold increases in the mEH and rGSTA2/3/5 mRNA levels relative to untreated animals, dexamethasone treatment (1 ㎎/㎏, p.o.) resulted in 64％-96％ decreases in the mRNA levels at 24 hr. The inducible rGSTM1/2 mRNA levels in the vitamin C/E treated rats were ∼50％ suppressed by dexamethasone. Although vitamin C and/or E treatment (200 ㎎/㎏/day, p.o., 2 days) improved the 30-day survival rates of the 8Gy γ-irradiated mice from 39％ up to 74％, the improved survival rate of γ-irradiated animals was reduced to 30％ by dexamethasone pretreatment (1 ㎎/㎏/day, 2 days). The mean survival time of dexamethasone-treated animals was reduced to ∼2days from 14days in the animals with total body irradiation alone. No significant hematologic changes were observed in mice at 10 days after dexamethasone plus γ-irradiation, as compared with irradiation alone. These results demonstrate that: dexamethasone substantially suppresses radiation-inducible mEH, rGSTA and rGSTM expression in the liver, vitamins C/E exhibit radioprotective effects without enhancing radiation-inducible mEH and GST gene expression; and inhibition of radiation inducible mEH and rGST gene expression in the vitamin C and E treated animals by dexamethasone was highly correlated with reduction in the survival rate and the mean survival time of γ-irradiated animals.