The Effect of Particle Size on the Cytotoxicity of Amorphous Silicon Dioxide: An in Vitro Toxicological Study.

INTRODUCTION: Amorphous silicon dioxide (A-SiO2) is abundant in the Earth's crust, the A-SiO2 nano and microparticles are released into the air through industrial and manufacturing activities. Due to the limited available toxicological information, the objective of the present study was to evaluate the toxicity of different sizes of A-SiO2 particles on the A549 cell-lines in an in vitro study. MATERIALS AND METHODS: The A-SiO2 particles in two categories of nano (10-100 nm) and micro (< 5um) were used in this study. The human lung A549 cell-line was exposed to either nano- or micro-sized A-SiO2 particles at 10, 50, 100, and 250 µg/ml, and the effects were investigated. RESULTS: The cytotoxicity of A-SiO2 nano and microparticles in both 24- and 72-hour exposure times resulted in decreased cell survival, mitochondrial membrane potential, and increased ROS generation which was concentration-time dependent (P <0.05) but glutathione content was not affected in a time-dependent manner. Cytotoxicity of nanoparticles, contrary to the previous study, was not higher than microparticles in the comparable dose and exposure times. CONCLUSION: The rate of ROS generation in the A549 cell-line exposed to A-SiO2 nanoparticles was higher than microparticles. And at the same time, cell survival for exposed cells to A-SiO2 nano and microparticles were higher for nanoparticles in shorter exposure periods and was inversely concentration- and time-dependent. Further studies on exploring the effect of size and its possible toxic mechanism are recommended to achieve a more credible risk assessment.

Synthesis and Molecular-cellular Mechanistic Study of Pyridine Derivative of Dacarbazine.

Dacarbazine is an antitumor prodrug which is used for the treatment of malignant metastatic melanoma and Hodgkin's disease. It requires initial activation in liver through an N-demethylationreaction. The active metabolite prevents the progress of disease via alkylation of guanine bases in DNA strands. In order to investigate the importance of imidazole ring and its dynamictautomerization in anticancer activity of dacarbazine, a pyridine analog of this drug was synthesized and the cytotoxic activity and cellular-molecular mechanisms of action for this compound were compared with those of dacarbazine. EC50 values for dacarbazine and the pyridine analog were found to be 56 µM and 33 µM respectively. Both dacarbazine and the pyridine analog resulted in formation of reactive oxygen species (ROS) upon their addition to the isolated rat hepatocytes. They also decreased the mitochondrial membrane potential and causedlysosomal membrane rupture. Cytotoxicity was prevented by ROS scavengers and antioxidants. Cytotoxicity wasalso prevented by CYP450 inhibitors, lysosomalinactivators and MPT (Mitochondrial Permeability Transition Pore) blockers.