Nitrogen monoxide (NO) plays a key role in the cytotoxic mechanisms of activated macrophages against tumour cells by inducing iron (Fe) release. Recently, we have showed that glutathione S-transferase P1-1 (GST P1-1) prevented the release of Fe via MRP1 in NO-treated neoplastic cells by sequestering NO as DNICs (dinitrosyl-dithiol iron complexes; J. Biol. Chem. 2012;287:607-18; J. Biol. Chem. 2012;287:6960�68), leading to increased cell survival. Hence, our results suggest the existence of a novel NO storage and transport system mediated by GST P1-1 and MRP1 that was vital in the protection against NO cytotoxicity. Based on our findings, we have further explored the physiological roles of GSTs in NO and Fe metabolism. Firstly, we examined whether other GST isoforms bind DNICs. Down-regulation of GST A1-1 and/or GST M1-1 expression in human hepatoma cells resulted in significant (p<0.001) increase in NO mediated Fe release, suggesting that other GST isoforms are also involved in tissue specific DNIC-binding and cellular NO storage. Significantly, GST P1-1 and MRP1 are both upregulated in activated macrophages, suggesting that these two proteins were pivotal in protecting the macrophage from the high concentrations of NO it produces. Furthermore, silencing of GST P1-1 expression in human umbilical vein endothelial cells (HUVECs), led to an increase in NO-induced Fe release, suggesting that it is also involved in NO storage in HUVECs. Coupled with the fact that polymorphisms in GSTs correlate with blood pressure dys-regulation (Hypertension. Res. 2008; 31:1015-19; Clinica. Chimica. Acta. 2009; 399:92-96), these results could have crucial implications for understanding the regulation of blood pressure. Taken together, GSTs and MRP1 formed an integrated system for NO storage and transport that play critical physiological roles.

Glutathione S-transferase and MRP1 form an integrated system involved in the storage and transport of nitric oxide in cells

248th National Meeting (2014)

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