Protective effects of cimetidine on radiation-induced micronuclei and apoptosis in human peripheral blood lymphocytes.
The radioprotective effects of cimetidine, which has been used clinically as an antagonist of H2 receptor, on radiation-induced micronuclei and apoptosis in human peripheral blood lymphocytes (PBL) prepared from healthy donors were studied. Cells were treated with cimetidine before or after X-irradiation, and then cytokinesis-blocked micronucleus assay and flow cytometry for measurement of phosphatidylserine externalization were utilized to evaluate the radiation-induced cytogenetic damage and apoptosis. The protective effect of preirradiation treatment of cimetidine on radiation-induced micronuclei was dependent on the concentration. The maximum protection rates of cimetidine (1 mM) on frequencies of micronuclei were 38.8 and 30.2% for cells treated before and after X-irradiation (5 Gy), respectively. Protective effects of pre- and post-irradiation treatment with cimetidine on radiation-induced early apoptosis and decreased activity of caspase-3 were observed. A study of electron paramagnetic resonance-spin trapping with 5,5'-dimethyl-1-N-oxide revealed that the rate constant of cimetidine with radiation-induced OH radicals is about 4.5 x 10(9) l/mol/s. Cimetidine did not significantly increase the intracellular concentration of glutathione. These results suggest that cimetidine suppresses radiation-induced micronuclei and apoptosis via OH radical scavenging and an intracellular antioxidation mechanism. Cimetidine appears to be a useful candidate for the future development of post-irradiation radioprotectors.
Kojima
Yasuo
Y
Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Kondo
Takashi
T
Zhao
Qing-Li
QL
Shoji
Miki
M
Futatsuya
Ryusuka
R
D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000528:radiation effects*; D002927:Cimetidine / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects*; D015162:Micronucleus Tests / Q000379:methods*; D011837:Radiation-Protective Agents
D011837:Radiation-Protective Agents; D002927:Cimetidine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione