TY - JOUR T1 - Approaches Toward Studying Genotoxicity and Potential Carcinogenicity of Metal Compounds In Vitro JF - PDA Journal of Pharmaceutical Science and Technology JO - PDA J Pharm Sci Technol SP - 231 LP - 237 VL - 37 IS - 6 AU - Max Costa Y1 - 1983/11/01 UR - http://journal.pda.org/content/37/6/231.abstract N2 - Crystalline NiS, a potent carcinogen in experimental animals, and amorphous NiS a compound having similar physical and chemical properties as crystalline NiS but lacking carcinogenic activity were used as model compounds to study the mechanism of cell transformation. Crystalline NiS particles were potent inducers of transformation in cultured Syrian Hamster Embryo cells whereas amorphous NiS particles were not active in transforming cells. Crystalline NiS particles were actively phagocytized by cultured facultative phagocytes (nonprofessional phagocytes) which were the target cells for transformation while amorphous NiS particles were not taken up. Amorphous NiS particles had a positive surface charge while crystalline NiS particles possess a negative surface charge. Chemical reductive of amorphous NiS with LiALH4 resulted in the acquisition of a more negative surface charge allowing the particles to be phagocytized more and this was associated with a level of transforming activity proportional to the uptake. Intracellularly the phagocytized NiS particles dissolved in the cytoplasm more rapidly than their dissolution extracellular and generated intracellular ionic nickel. This process allows ionic nickel to enter the nucleus since nickel in a particulate state was not able to cross the nuclear membrane. Treatment of cells with crystalline NiS or sufficient quantities of NiCl2 resulted in DNA single strand breaks. DNA-protein crosslinks and in the induction of DNA repair. Assessing the extent and nature of these lesions represents a very sensitive and reliable method to examine potential genotoxicity of chemical agents. ER -