Molecular mechanism of Cr(VI)-induced carcinogenesis.
Shi-X; Castranova-V; Vallyathan-V
Metal ions in Biology and Medicine, 2000, J. A. Cantano, P. Collery, G. Vernet, R. B. Finkelman, H. Gibb, J. C. Etienna, eds., Paris, France: John Libbey Eurotext, 2000 Jan; 6:110-112
We hypothesize that reduction of Cr(VI) to its low oxidation states, Cr(V) and Cr(IV), is an important step in the mechanism of Cr(VI)-induced carcinogenesis. These chromium intermediates are able to generate reactive oxygen species (ROS), which initiate Cr(VI)-induced carcinogenesis. Through free radical reactions, Cr(VI) can activate multiple carcinogenic processes. (1) Cr(VI) causes activation of nuclear transcription factor kappa B (NF -KB). Among ROS, hydroxyl radicals (OH) are responsible for Cr(VI)-induced NF-KB activation. (2) Cr(VI) is able to activate activator protein-1 (AP-l). (3) Cr(VI) causes p53 activation and OH radicals function as messengers for the activation of this tumor suppressor protein. (4) Cr(VI) is capable of inducing apoptosis via both p53 and ROS-mediated reactions. (5) Cr(VI) causes over-expression of oncogenes (jun-B and raf), up-regulation of antioxidants (glutathione peroxidase), activation of certain enzymes involved in mitogen-activated protein kinase (MAP kinase) signal pathways (MAPKAP kinase), stimulation of enzymes involved in cell cycle control and checkpoint mechanisms (checkpoint suppressor 1), and activation of enzymes responsible for Cr(VI) reduction, such as NAD(P)H dependent dihydrolipoamide dehydrogenase. Cr(VI)-containing compounds are considered to be well established carcinogens (1). They are potent inducers of tumors in experimental animals and active agents in causing DNA damage such as DNA strand breakage. We have hypothesized that reduction of Cr(VI) to its low oxidation states, Cr(V) and Cr(IV), is an important step (2). These chromium intermediates are able to generate ROS, which initiate Cr(VI)-induced carcinogenesis. This article summarizes our studies on Cr(VI) reduction and related free radical generation and the role of free radical reactions in various potential mechanisms for the initiation of carcinogenesis induced by this metal.
Carcinogenesis; Carcinogens; Carcinogenicity; Chromium-compounds; Free-radicals; Oncogenesis; Oncogenic-agents; Oncogenicity; Antioxidants; Metals; Free-radical-generation; Laboratory-animals; Animals; Animal-studies
Abstract; Conference/Symposia Proceedings
Cantano-JA; Collery-P; Vernet-G; Finkelman-RB; Gibb-H; Etienna-JC
Metal ions in Biology and Medicine