Earlier we have shown relationship between cytotoxicity

Earlier, we have shown relationship between cytotoxicity and receptor degeneration in Sunitinib having specific neurotransmitter receptors (Siddiqui et al., 2008). In the present study, exposure to 4-HNE reduced expression of DA-D2 receptors in PC12 cells which was found to be concentration dependent and not with time. It is possible that after initial exposure of PC12 cells to 4-HNE for 1h, physiological remodeling enhances the defense system of the cells which allows them to resist for longer exposure periods, i.e., 4 or 8h. Interestingly, the decrease in the expression of DA-D2 receptor protein suggests that neurotransmitter receptors in PC12 cells are physiologically sensitive. It also supports our earlier findings of the degeneration of dopaminergic neurons/dopamine receptors at higher concentrations of 4-HNE by inducing signaling pathways including oxidative stress (Liang et al., 2007, Gallagher et al., 2007, Arakawa et al., 2007). Therefore, the decrease in the expression of DA-D2 receptor proteins and 4-HNE induced cytotoxicity through oxidative stress mediated signaling pathways cannot be ignored (Siddiqui et al., 2008). The expression of GSTP1-1 was found to be associated with the availability of GSH as substrate in PC12 cells. It reflects the anti-oxidant potential of GSH against 4-HNE in PC12 cells. Similar findings have also been reported for GST isoenzymes in SH-SY5Y neuronal cells exposed to 4-HNE (Xie et al., 2001, Yadav et al., 2008). Over expression of GSTP1-1 was observed while PC12 cells were externally supplemented with GSH (5mM) for 4 and 8h. Both over and under expression of GSTP1-1 against HNE exposure has been reported in a variety of cells (Dabrowski et al., 2006, Zhang et al., 2002). The variation in the expression has been suggested due to different mechanisms regulating the GSTP1-1 gene at transcription and translation or even post-translation levels in cells of different origin (Peklak-Scott et al., 2008). The results of the present study exhibit that PC12 cells are vulnerable to higher concentrations of 4-HNE. The basal expression of GSTP1-1 and its responsiveness to external supplementation of GSH in cultured PC12 cells is also noteworthy. The study also indicates usefulness of PC12 cells as in vitro tool to understand the toxicant–cell interactions.
Acknowledgments