ANTIOXIDANT ACTION VIA P53-MEDIATED APOPTOSIS

The biological effects of antioxidants are often considered in terms o f their effects on oxygen or lipid radicals, However, antioxidants can also exert their effects through altering the cellular redox potentia l, Herein, we report that sulfur-containing antioxidants such as N-ace tylcysteine and dimereaptopropanol induced apoptosis in several transf ormed cell Lines and transformed primary cultures but not in normal ce lls. In contrast, chain-breaking antioxidants such as vitamin E lacked this activity, An increased glutathione level was not required for ap optosis; however, all apoptosis-inducing antioxidants elevated the tot al cellular thiol levels. Antioxidant-induced apoptosis required the p 53 tumor suppressor gene, N-Acetylcysteine elevated p53 expression pos ttranscriptionally by increasing the rate of p53 mRNA translation rath er than by altering the protein stability. The p53 induction occurred in normal cells, These observations indicate a redox sensor for p53 in duction in vivo, with additional transformation-specific information b eing required for apoptosis. Manipulating p53-dependent apoptosis with nontoxic antioxidants may have a direct clinical application.