APOPTOTIC VS NONAPOPTOTIC CYTOTOXICITY INDUCED BY HYDROGEN-PEROXIDE

The regulation of cellular cytotoxicity induced by hydrogen peroxide ( H2O2) over a wide concentration range was assessed. Three distinct pat terns were detected: the highest concentrations (>10 mM) rapidly induc ed a necrotic form of death characterized by smeared patterns of DNA d igestion and morphological evidence of primary cytoplasm and plasma me mbrane damage; In contrast, 10 and 5 mM H2O2 induced endonucleosomal D NA digestion 2 concurrently with cytotoxicity and target cell death wa s associated with morphologic evidence of apoptosis. Apoptosis was inh ibited by cycloheximide, emetine, aminobenzamide (ABA), aurintricarbox ylic acid, and calcium depletion. The lowest concentrations of H2O2 (0 .5 and 0.1 mM)-induced delayed cytotoxicity (at 24 or 48 hr), which wa s not associated with DNA ladder formation or morphologic evidence of apoptosis, but was inhibited by ABA. Enforced expression of BCL-2 indu ced resistance to 0.5 and 0.1 mM H2O2 but had no effect on cytotoxicit y induced by 5 and 10 mM. Exposure of isolated nuclei to H2O2 in the a bsence of calcium or magnesium failed to induce endonucleosomal fragme ntation. These data indicate that distinct pathways of H2O2-induced cy totoxicity can be distinguished by their different concentration depen dences, and that BCL-2 can protect against some forms of H2O2-induced cytotoxicity. Copyright (C) 1996 Elsevier Science Inc.