PROLIFERATION OF MOUSE FIBROBLASTS INDUCED BY 1,2-DIMETHYLHYDRAZINE AUTOXIDATION - ROLE OF IRON AND FREE-RADICALS

Activation of 1,2-dimethylhydrazine (DMH) by prolonged auto-oxidation (24-h) induced proliferation of mouse fibroblasts at low hydrazine con centrations (0.1-1.0 mM) as determined by [H-3-methyl]-thymidine uptak e of confluent quiescent cells. Incubations were performed under condi tions in which alkyl radicals are slowly formed by DMH auto-oxidation. The proliferative stimulus induced by DMH auto-oxidation complements that induced by insulin, PMA, and EGF. Inhibition by the iron chelator s, o-phenanthroline and desferrioxamine, demonstrates that the inducti on of the proliferative effect is dependent on simple iron complexes. Proliferation was also inhibited by superoxide dismutase, catalase, an d mannitol, implicating reactive oxygen species, although superoxide d ismutase and catalase also inhibited alkyl radical formation, as deter mined by spin-trapping. These results suggest that cell proliferation induced by DMH auto-oxidation is mediated by reactive oxygen species, mainly the hydroxyl radical, and is dependent on simple iron complexes , possibly involving the Fenton reaction. (C) 1997 Academic Press.