title: Glutathione S-transferase and MRP1 form an integrated system involved in the storage and transport of dinitrosyl-dithiolato iron complexes in cells.
abstract: Nitrogen monoxide (NO) is vital for many essential biological processes as a messenger and effector molecule. The physiological importance of NO is the result of its high affinity for iron in the active sites of proteins such as guanylate cyclase. Indeed, NO possesses a rich coordination chemistry with iron and the formation of dinitrosyl-dithiolato iron complexes (DNICs) is well documented. In mammals, NO generated by cytotoxic activated macrophages has been reported to play a role as a cytotoxic effector against tumor cells by binding and releasing intracellular iron. Studies from our laboratory have shown that two proteins traditionally involved in drug resistance, namely multidrug-resistance protein 1 and glutathione S-transferase, play critical roles in intracellular NO transport and storage through their interaction with DNICs (R.N. Watts et al., Proc. Natl. Acad. Sci. USA 103:7670-7675, 2006; H. Lok et al., J. Biol. Chem. 287:607-618, 2012). Notably, DNICs are present at high concentrations in cells and are biologically available. These complexes have a markedly longer half-life than free NO, making them an ideal "common currency" for this messenger molecule. Considering the many critical roles NO plays in health and disease, a better understanding of its intracellular trafficking mechanisms will be vital for the development of new therapeutics.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: H C
authors.initials: HC
authors.lastname: Lok
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Richardson
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: D S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: D J R
authors.initials: DJ
authors.lastname: Lane
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D001692:Biological Transport; D019008:Drug Resistance, Neoplasm; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D058085:Iron Compounds / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism*
chemical_list: D005982:Glutathione Transferase; D007501:Iron; D058085:Iron Compounds; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D009589:Nitrogen Oxides; C420456:dinitrosyl iron thiosulfate; C421109:multidrug resistance-associated protein 1
keywords: Dinitrosyl–dithiolato iron complexes; Free radicals; Nitrogen monoxide; Protein metal ion interactions