Radioprotective effects of 2-(allylthio)pyrazine an experimental chemopreventive agent: effects on detoxifying enzyme induction.
2-(Allylthio)pyrazine (2-AP), which is effective in suppressing constitutive and inducible cytochrome P450 2E1 expression, exhibits hepatoprotective and chemopreventive effects. The radioprotective effects of 2-AP were examined in animals in association with the expression of microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs). 2-AP pretreatment (100 mg/kg/day, for 2 days) prior to total body irradiation (TBI) at the dose of 8 Gy increased the 30 day survival rate of mice to 91% from 48% in TBI alone. 2-AP caused an increase in the mean survival time of mice exposed to 9 Gy of TBI. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray radiation resulted in hepatocyte degeneration in the surviving animals at day 1 through day 22 with certain extents of necrosis observed at early times, whereas 2-AP pretreatment protected the liver against ionizing radiation with no hepatic necrosis being observed. Mice irradiated at the dose of 8 Gy showed time-related decreases in the counts of WBC, RBC and platelet. 2-AP treatment, however, failed to protect the peripheral blood cells against gamma-irradiation and resulted in no improvement in the ratio of myeloid to erythroid bone marrow cells, as compared to TBI alone. Northern blot analysis revealed that exposure of mice to 8 Gy of TBI plus 2-AP exhibited greater mEH and mGSTA3 mRNA levels in the liver than those with TBI alone, although mGSTP1 mRNA level failed to be altered. Studies were also extended to determine the effects of 0.5 Gy gamma-irradiation in combination with 2-AP on the expression of hepatic mEH and GST genes in rats. Whereas mEH, rGSTA2, rGSTA3 and rGSTA5 mRNA levels were elevated 2- to 2.8-fold at 24 h after 2-AP treatment at the dose of 30 mg/kg, rats exposed to both 2-AP and 0.5 Gy of irradiation showed greater relative increases in the mRNAs. 2-AP enhanced the mEH and rGSTA2 gene expression to greater extents at day 1 after irradiation than after 3-5 consecutive daily treatment. The radiation-inducible mRNA levels of rGSTA3/5 and rGSTM1/2 were affected less by 2-AP pretreatment than were those of mEH and rGSTA2. These results demonstrate that 2-AP exhibits radioprotective efficacy against gamma-ray ionizing radiation in both mice and rats, which might be associated with enhanced expression of mEH and GST genes, but not with hematological improvement.
Kim
S G
SG
College of Pharmacy, Duksung Women's University, Seoul, South Korea. sgkim@center.duksung.ac.kr
Nam
S Y
SY
Kim
C W
CW
Cho
C K
CK
Kim
N D
ND
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
C104935:2-(allylthio)pyrazine; D004791:Enzyme Inhibitors; D011719:Pyrazines; D011837:Radiation-Protective Agents; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases