Clastogenic action of hydroperoxy-5,8,11,13-icosatetraenoic acids on the mouse embryo fibroblasts C3H/10T1/2.
Phorbol 12-myristate 13-acetate induces the release of a low molecular weight clastogenic factor from monocytes. Hydroperoxy-5,8,11,13-icosatetraenoic acids represent major components of clastogenic factor. We report that several isomeric hydroperoxy-5,8,11,13-icosatetraenoic acids efficiently induce DNA strand breakage and/or alkali-labile sites in the mouse embryo fibroblasts C3H/10T1/2. Fe chelation by desferrioxamine suppresses breakage by approximately equal to 42% indicating the participation of Fe-catalyzed radical reactions. An additional 37% inhibition is observed upon addition of the Ca2+ chelators EGTA and quin-2. This result suggests that hydroxyperoxy-5,8,11,13-icosatetraenoic acid may activate a Ca2+-dependent nuclease. The addition of the antioxidant enzymes CuZn-superoxide dismutase and catalase had no effect, while glutathione peroxidase suppressed strand breakage by 90%. To our knowledge, our results yield a first insight into the mechanism of action of monocyte clastogenic factor and the role of inflammation in tumor promotion.
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D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D004249:DNA Damage; D003676:Deferoxamine / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000494:pharmacology*
D001095:Arachidonic Acids; D009153:Mutagens; D003676:Deferoxamine; D002118:Calcium