In vivo radioprotective effects of oltipraz in gamma-irradiated mice.
Previous studies in this laboratory have shown that oltipraz (Olt), a chemopreventive agent, enhances radiation(Rad)-inducible glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) expression in the liver. The present study was designed to investigate the in vivo radioprotective effect of Olt in ICR mice exposed to a lethal dose of Rad. The 30-day survival rate of mice irradiated at the dose of 8 Gy was substantially increased to 91% by Olt pretreatment (100 mg/kg/day for 2 days), compared with 48% in animals irradiated alone. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray Rad resulted in hepatocyte degeneration in the surviving animals from Day 1 through Day 22 after irradiation with certain degrees of necrosis observed at early times, whereas Olt treatment provided protection of the liver against irradiation with no hepatic necrosis noted. Mice irradiated at the dose of 8 Gy exhibited time-related decreases in the white blood cell (WBC), red blood cell (RBC), and platelet counts with maximal reduction noted at Day 10. Animals irradiated with Olt treatment showed no difference in peripheral blood cell counts or in the ratio of myeloid to erythroid bone marrow cells, compared with those irradiated alone. Northern RNA blot analysis showed that treatment of mice with Olt at the dose of 100 mg/kg in combination with 8 Gy irradiation resulted in 12-fold increases in hepatic mEH and mGSTA3 mRNA levels at 24-hr post-treatment, whereas mGSTP1 mRNA levels were not altered. The mRNA levels for mEH and mGSTA3 were elevated after exposure of animals to both Olt and 8 Gy-gamma ray to a greater extent than after irradiation alone. The enhanced survival rate (91%) in 8 Gy-irradiated animals after treatment with Olt (100 mg/kg/day for 2 days) was completely reversed by concomitant pretreatment with dexamethasone (Dexa) (0.1 and 1 mg/kg/day for 2 days), a known inhibitor of mEH and GST expression, resulting in a 42% and 28% survival rate, respectively. Mice irradiated after dexamethasone treatment at a dose of 1 mg/kg showed a reduced mean survival time compared with those treated with 0.1 mg/kg of dexamethasone (9 vs 14 days). The current study demonstrates that Olt is effective in increasing the survival rate of mice against ionizing Rad and that protective effects of Olt associated with enhanced expression of mEH and GST genes may represent its radioprotective efficacy.
Kim
S G
SG
College of Pharmacy, Duksung Women's University, Seoul, Korea. sgkim@center.duksung.ac.kr
Nam
S Y
SY
Kim
C W
CW
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011719:Pyrazines / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015996:Survival Rate; D013871:Thiones; D013876:Thiophenes
D011719:Pyrazines; D011837:Radiation-Protective Agents; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D003907:Dexamethasone; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases