Protection against chromium (VI)-induced oxidative stress and apoptosis by Nrf2.
Toxicologist 2010 Mar; 114(1):433
Nrf2, an antioxidant-activated cap 'n' collar bZip transcription factor, has recently emerged as a critical regulator of cellular defense against oxidative stress, a prominent component in the pathogenesis of a broad range of disease and chemical toxicity including metal-induced cancer and toxicity. Chromium (Cr) is a major environmental/ occupational toxic metal and an established human carcinogen. Exposure to Cr(VI) elicits respiratory cancer and multi-organ toxicity including renal damage, pulmonary fibrosis, allergy, and asthma in humans. At a cellular level, Cr(VI) induces prominent oxidative stress and apoptosis. Data demonstrated that Nrf2 is critically involved in the cellular response to Cr(VI)-induced ROS production and cell death. Cr(VI) at a non-toxic concentration activates Nrf2 by interacting with critical cysteine residues of Nrf2 and Keap1--a cytoplasmic Nrf2-binding partner that controls the degradation of Nrf2 in the absence of an inducer. Activated Nrf2 mediates induction of a battery of cytoprotective genes encoding phase 2 detoxification enzymes and antioxidative proteins that inhibit ROS production and apoptosis by Cr(VI). Targeted disruption or siRNA-mediated knockdown of Nrf2 markedly elevated ROS production under basal conditions and in the presence of Cr(VI) that involves altered oxygen and energy metabolism in the mitochondria. Nrf2 potentially coordinate a network of protective mechanisms against mitochondrial damage by toxic metals. In summary, Nrf2 protects against chromium (VI)-induced apoptosis via a mechanism that may also be applicable to other metals such as arsenic and cadmium.
Biological-effects; Cancer; Cell-biology; Chemical-reactions; Exposure-assessment; Exposure-levels; Exposure-methods; Metal-compounds; Metal-industry; Metallic-poisoning; Metal-poisoning; Metalworking-industry; Pathogenicity; Physiological-effects; Statistical-analysis; Toxic-effects; Toxic-materials; Toxicopathology
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah