ANTIOXIDANT ACTIVITY OF LAZAROID (U-75412E) AND ITS PROTECTIVE EFFECTS AGAINST CRYSTALLINE SILICA-INDUCED CYTOTOXICITY

Lazaroids (21-amino steroids) are believed to be powerful scavengers o f reactive oxygen species (ROS) and inhibitors of lipid peroxidation. Crystalline silica, a potent cytotoxic agent, causes pulmonary fibrosi s in experimental animals and humans. ROS have been previously shown t o be involved in crystalline silica-induced pulmonary injury and infla mmation. In the present study, the reaction rate of lazaroid (U-75412E ) with hydroxyl radical ((OH)-O-.) generated by Fenton reaction (Fe(II ) + H2O2 --> Fe(III) + OH- + (OH)-O-.) was investigated using ESR spin -trapping competition reactions. The reaction rate constant was found to be 1.0 x 10(10) M(-1)s(-1), which was comparable with those of othe r efficient (OH)-O-. radical scavengers. As indicators of crystalline silica-induced cytotoxicity and its protection by this antioxidant laz aroid (U-75412E) we measured lactate dehydrogenase, N-acetyl-beta-D-gl ucosaminidase, superoxide dismutase, glutathione peroxidase, and hydro gen peroxide released from rat alveolar macrophages; Lipid peroxidatio n, a prominent manifestation of (OH)-O-. radical-induced cell injury, was also measured to evaluate the protective value of lazaroid. Alveol ar macrophages treated with lazaroid (U-75412E) before crystalline sil ica exposure were protected against cell injury and lipid peroxidation as demonstrated by those indicators. Lazaroid (U-75412E) scavenges (O H)-O-. radicals generated by crystalline silica-mediated reaction from H2O2 and inhibits lipid peroxidation in macrophages induced by these particles. (C) 1998 Elsevier Science Inc.