CHROMIUM-INDUCED GENOTOXICITY AND APOPTOSIS - RELATIONSHIP TO CHROMIUM CARCINOGENESIS (REVIEW)

The adverse health effects linked with chromium (Cr) exposure, the rol e of solubility and chemical speciation of Cr compounds, and the diver se cellular and molecular effects of Cr make the study of Cr carcinoge nesis and toxicology very interesting and complex. Certain Cr compound s are prominent metal carcinogens in both occupational and environment al settings. Inhaled particulate forms of hexavalent Cr [Cr(VI)] cause lung cancer as well as lung toxicity. Some of the important factors i n determining the biological outcome of Cr exposure include the bioava ilability, chemical speciation and solubility of Cr compounds, intrace llular reduction, and interaction of Cr with DNA. The stable oxidation states of Cr found in nature are Cr(III) and Cr(VI). Cr(III) is unabl e to enter cells but Cr(VI) enters into cells through membrane anionic transporters. Intracellular Cr(VI) is metabolically reduced to the ul timate Cr(III). Cr(VI) does not react with macromolecules such as DNA, RNA, proteins and lipids. However, both Cr(III) and the reductional i ntermediate Cr(VI) are capable of co-ordinate covalent interactions wi th macromolecules. At the genomic level, Cr genotoxicity manifests as gene mutations, several types of DNA lesions and inhibition of macromo lecular synthesis. At the cellular level, Cr exposure may lead to cell cycle arrest, apoptosis, premature terminal growth arrest, or neoplas tic transformation. Cr-induced DNA-DNA interstrand crosslinks (DDC),,t he tumor suppressor gene p53 and oxidative processes are some of the m ajor factors that may play a significant role in determining the cellu lar outcome in response to Cr exposure. We have utilized cellular, mol ecular, pharmacological, and genetic approaches to understand the inte rrelationship between Cr-induced genotoxicity, apoptosis and carcinoge nesis. This review is based on the results and inferences of this rese arch. We hope this review will clarify existing concepts and also intr oduce novel perspectives in chromium carcinogenesis research.