Role of p53 tumor suppressor gene in the toxicity of TCDD, endrin, naphthalene, and chromium (VI) in liver and brain tissues of mice

It has been postulate that tumor suppressor genes are involved in the casca de of events leading to the toxicity of diverse xenobiotics. Therefore, we have assessed the comparative effects of 0.01, 0.10, and 0.50 median lethal doses (LD50) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), endrin, naphth alene, and sodium dichromate (VI) [Cr(VI)] on lipid peroxidation, DNA fragm entation, and enhanced production of superoxide anion (cytochrome c reducti on) in liver and brain tissues of p53-deficient and standard C57BL/6NTac mi ce to determine the role of p53 gene in the toxic manifestations produced b y these diverse xenobiotics. In general, p53-deficient mice are more suscep tible to all four xenobiotics than C57BL/6NTac mice, with dose-dependent ef fects being observed. Specifically, at a 0.50 LD50 dose, naphthalene and Cr (VI) induced the greatest toxicity in the liver tissue of mice, and naphtha lene and endrin exhibited the greatest effect in the brain tissue. At this dose, TCDD, endrin, naphthalene, and Cr(VI) induced 2.3- to 3.7-fold higher increases in hepatic lipid peroxidation and 1.8- to 3.0-fold higher increa ses in brain lipid peroxidation in p53-deficient mice than in C57BL/6NTac m ice. At a 0.10 LD50 dose, TCDD, endrin, naphthalene, and Cr(VI) induced 1.3 - to 1.8-fold higher increases in hepatic lipid peroxidation and 1.4- to 1. 9-fold higher increases in brain lipid peroxidation in p53-deficient mice t han in C57BL/6NTac mice. Similar results were observed with respect to DNA fragmentation and cytochrome c reduction (superoxide anion production). For example, at the 0.10 LD50 dose, the four xenobiotics induced increases of 1.6- to 3.0-fold and 1.5- to 2.1-fold in brain and liver DNA fragmentation, respectively, and increases of 1.5- to 2.3-fold and 1.4- to 2.5-fold in br ain and liver cytochrome c reduction (superoxide anion production), respect ively, in p53-deficient mice compared with control C57BL/6NTac mice. These results suggest that the p53 tumor suppressor gene may play a role in the t oxicity of structurally diverse xenobiotics. (C) 2000 Elsevier Science Inc.