Involvement of calcium-dependent protein kinase C in arsenite-induced genotoxicity in Chinese hamster ovary cells.
Arsenic is the first metal to be identified as a human carcinogen. Arsenite, one inorganic form of arsenic, has been found to induce sister chromatid exchange, chromosome aberrations, and gene amplification in a variety of in vitro systems. In this study of arsenite-induced genotoxicity represented a micronuclei production in Chinese hamster ovary cells (CHO-K1), we found that the calcium channel blocker, verapamil, can potentiate arsenite-induced micronuclei. And after arsenite treatment, the elevation of intracellular calcium was observed. When extracellular calcium was depleted during arsenite treatment, the arsenite-induced micronuclei formation was significantly suppressed. These data indicated that a calcium ion plays an essential role in arsenite-induced genotoxicity. Further, it was found that the cotreatment of arsenite and a calcium ionophore, A23187, can increase the micronuclei induction. In contrast, pretreatment of the intracellular calcium chelator, quin 2, significantly inhibited micronuclei production of arsenite administration. In addition, we measured the activity of calcium- and phospholipid-dependent protein kinase C (PKC) and found that arsenite can activate PKC activity in a dose-dependent manner. Subsequently, some PKC activators and inhibitors were applied to investigate the involvement of PKC on arsenite-induced micronuclei formation. It was found that H7, a PKC inhibitor, can depress but TPA, a PKC activator, can enhance arsenite-induced micronuclei significantly. These data indicated that arsenite exposure perturbs intracellular calcium homeostasis and activates PKC activity. As a result, the activation of PKC activity may play an important role in arsenite-induced genotoxicity.
Liu
Y C
YC
Institute of Radiation Biology, National Tsing-Hua University, Hsinchu, Taiwan, Republic of China.
Huang
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001149:Arsenates / Q000633:toxicity*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002869:Chromosome Aberrations / Q000502:physiology*; D006224:Cricetinae; D004789:Enzyme Activation; D005784:Gene Amplification; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006706:Homeostasis; D015162:Micronucleus Tests; D011493:Protein Kinase C / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases
D000255:Adenosine Triphosphate; D001149:Arsenates; D002118:Calcium; D002374:Catalase; D005978:Glutathione; D005982:Glutathione Transferase; D011493:Protein Kinase C; D011494:Protein Kinases; D014700:Verapamil; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C025657:arsenic acid