Involvement of clock genes against copper-induced diurnal toxicity in mice

<p>Background: We have developed the chronotoxicology considering the relationship between injection time and the toxic severity of medicines or chemicals. We previously demonstrated that metal-induced chrono-toxic effects were different depending on metal, respectively. As for copper, mice were susceptible at evening (18:00 and 22:00), while slightly resistant at midnight (6:00) and light phase (10:00 and 14:00). The purpose of present research is to compare injection times (one shot vs multiple shots) and identify the cellular molecule(s) involving this chronotoxicity. </p><p>Results amd Discussion: We demonstrated that copper-induced toxicity at dark phase (22:00) is severe than that of light phase (10:00) in lethality and hepatic injury. This result suggests that copper-induced diurnal toxicity is not affected by injection time. We found that treatment with copper upregulated three kinds of clock gene (Ciart, Cry2, and Per1) levels in Hepa1-6 cells. We demonstrated that overexpression of Cry2 and Per1 potentiated copper-induced toxicity. Moreover, we showed that overexpression of Cry2 and Per1 modulated CTR1 (copper incorporation transporter), ATP7B (copper excretion transported), cleaved caspase-3 (apoptosis), and Cyclin E (cell cycle). These results suggest that modulation of copper transporter by Cry2 and Per1 potentiate copper-induced hepatic injury by accumulating copper in the liver.</p>