Clastogenic Action of Hydroperoxy-5,8,11,13-icosatetraenoic Acids on the Mouse Embryo Fibroblasts C3H/10T1/2

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 84; no. 4; pp. 990 - 994
• Main Authors: Ochi, Takafumi, Cerutti, Peter A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-02-1987; National Acad Sciences
• Subjects: Animals; Antioxidants; Arachidonic Acids - pharmacology; Biological and medical sciences; Biomechanical Phenomena; Calcium - metabolism; Cells; Deferoxamine - pharmacology; DNA; DNA Damage; Elution; Embryo, Mammalian - drug effects; Embryos; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Inflammation; Mice; Mice, Inbred Strains; Molecular and cellular biology; Monocytes; Mutagens - pharmacology; Prostaglandins; Superoxides; Vertebrata; Embryo; Mammalia; Monocyte; Mouse; Animal; Tumor promotor; Rodentia; Inflammation; Mechanism of action; Fibroblast
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.84.4.990

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 ≈ 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.