(2)     Nitric Oxide is Not Freely Diffusible in Cells, But Bound and Transported by GSTP1 and MRP1 as a Dinitrosyl-Dithiol Iron Complex

A second paradigm-shifting area is Richardson research (again elucidated over a period of 20 years) on a novel storage and transport system for nitric oxide (NO).  Nitric oxide was thought generally as a freely diffusible molecule in cells, as it is a small molecular weight diatomic gas actively involved in a wide variety of biological signaling functions including blood pressure control and the cytotoxic activity of macrophages against tumour cells.

However, in a series of innovative studies, Richardson demonstrated that the ability of NO to induce iron release from cells was coupled to glucose metabolism and the generation of glutathione (GSH) and ATP (Fig. 3). These studies led to the demonstration that NO acted somewhat like a chelator in cells to bind cellular iron to form a  dinitrosyl dithiol iron complex (DNIC) which was then actively transported out of cells.

In fact, in this case, the DNIC was then actively transported out of cells by the glutathione transporter, MRP1. These studies then led to the demonstration that the DNIC was bound to glutathione-S-transferase P1 (GSTP1) and could store DNICs to prevent their release by MRP1.  This transport and storage of NO as a DNIC “currency” was proven in tumour cells, but also NO-generating macrophages, where the cooperation between GSTP1 and MRP1 prevents NO-induced cytotoxicity.

This storage and transport system provides the cell with a mechanism to regulate NO and use its key signalling and effector roles, e.g., blood pressure regulation and the cytotoxic activity of macrophages