Glutathione transport

The y-glutamyl cycle enzymes are found in those tissues where glutathione transport into cells is an important function. Whereas glutathione is exported by most cells, it is... 

Atamna, H. Ginsburg, H. The malaria parasite supplies glutathione to its host cell-investigation of glutathione transport and metabohsm in human er5dhroc3ftes infected with Plasmodium falciparum. Eur. J. Biochem., 1997, 250 670-679. 

The MRP family of transporters is closely related and structurally similar to the MDR family (64/ 65). MRPl was initially identified in lung cellS/ which were known not to express P-gp. It has been shown to pump anionic compounds (as opposed to the cations pumped by P-gp). Substrates for MRPl include anionic natural products glutathione/ glucuronyl/ and sulfate conjugates and/ in some caseS/ neutral molecules coupled to glutathione transport without conjugation. In liver cellS/ MRPl is present on the sinusoidal surface of the hepatocyte. MRP2 is similar to MRPl/ except in its tissue distribution and localization. In liver cellS/... 

Peters, J.G., van Os, C.H., and Russel, F.G. (1999) Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by fhe rabbit multidrug resistance protein Mrp2 expressed in insect cells. Molecular Pharmacology, 56, 714—719. 

Akerboom T, Sies H (1990) Glutathione transport and its significance in oxidative stress. In Vina J (ed) Glutathione metabolism and physiological functions. CRC, Boca Raton, Florida, pp 45-55... 

Kondo T,Dale GL, Beutler E (1981) Studies on glutathione transport utilizing inside-out vesicles prepared from human erythrocytes. Biochim Biophys Acta 645 132 Srivastava SK, Beutler E (1969) The transport of oxidized glutathione from human erythrocytes. J Biol Chem 244 9... 

Kondo T, Murao M, Taniguchi N (1982) Glutathione S-conjugate transport using inside-out vesicles from human erythrocytes. Eur J Biochem 125 551 Lu SC, Kuhlenkamp J, Ge JL, Sun WM, Kaplowitz N (1994) Specificity and directionality of thiol effects on sinusoidal glutathione transport in rat liver. Mol Pharmacol 46 578-85... 

Lash LH, Jones DP (1984) Renal glutathione transport. Characteristics of the sodium-... 

Lash, L. H. 2005. Role of glutathione transport processes in kidney function. Toxicology and Applied Pharmacology 204 392-342. 

Lash, L.H. Jones, D.P. Renal glutathione transport characteristics of the sodium-dependent system in the basal-lateral membrane. J. Biol. Chem. 1984, 259, 14508-14514. 

Gao L, Kim KJ, Yankaskas JR, Forman HJ. Abnormal glutathione transport in cystic fibrosis airway epithelia. Am J Physiol 1999 277 L113. 

MDR-ABC Transporters. Figure 3 Detoxification cellular mechanisms. X, toxic compound X-OH, oxidized toxic compound GS-X, conjugated toxic compound OATP, organic anion transporting proteins CYPs, cytochromes GSH, glutathion UDPGIcUA, Uridine 5-diphosphoglucuronic acid PAPs, 3-phosphoadenylylsulfate. 

Apart from their catalytic function, at least one form of glutathione-5-trans-ferases has the function of simply binding xenobiotics and transporting them, without metabolism. In effect, this is an example of storage (see Section 2.3.3). The form in question is termed ligandin, and binding is associated with one particular subunit. Binding is not associated with catalytic activity. 

Glutathione not only plays an important role in phase 2 reactions but is also an intracellular reducing agent and is involved in the transport of certain amino acids into cells. 

The Na/K ATPase has been extensively purified and characterized, and consists of a catalytic a subunit of around 95 kDa and a glycoprotein 0 subunit of approximately 45 kDa (Skou, 1992). The functional transporter exists as a dimer with each monomer consisting of an a and /3 subunit. Hiatt aal. (1984) have su ested that the non-catalytic jS subunit may be involved in the cottect insertion of the a subunit into the lipid bilayer and, therefore, it is conceivable that a modification of the 0 subunit structure may be reflected by changes in the catalytic activity of the a subunit. Therefore, in studies involving the manipulation of tissue glutathione levels, alterations of intracellular redox state may have an effect on substrate binding at an extracellular site on this ion-translocating protein. 

If cellular redox state, determined by the glutathione status of the heart, plays a role in the modulation of ion transporter activity in cardiac tissue, it is important to identify possible mechanisms by which these effects are mediated. Protein S-,thiolation is a process that was originally used to describe the formation of adducts of proteins with low molecular thiols such as glutathione (Miller etal., 1990). In view of the significant alterations of cardiac glutathione status (GSH and GSSG) and ion-transporter activity during oxidant stress, the process of S-thiolation may be responsible for modifications of protein structure and function. 

Bannai, S. and Tateishi, N. (1986). Role of membrane transport in metabolism and function of glutathione in mammals. J. Membr. Biol. 89, 1-8. 

Garcia Ruiz, C., Fernandez Checa, J. and Kaplowitz, N. (1992). Bidirectional mechanism of plasma membrane transport of reduced glutathione in intact rat hepatocytes and membrane vesicles. J. Biol. Chem. 267, 2256-2264. 

The GSH reductase inhibitor l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) also promotes corneal swelling in the isolated cornea. The addition of GSH prevents the action of BCNU as the cornea needs a constant supply of NADPH for maintaining adequate concentrations of reduced glutathione for the detoxification of hydrogen peroxide. It has been shown that hydrogen peroxide and BCNU primarily affect the permeability of the endothelial cells rather than the active processes transporting sodium and chloride ions across the membrane (Riley, 1985). 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

Glutathione has specific transporters for its entry into mitochondria (as has iron, see later) such that any defects in its transport into the mitochondria will be important contributing factors in precipitating mitochondrial toxicity. Evidence that dicarboxylate and 2-oxoglutamate may be carriers for glutathione into the mitochondria has recently been published (Chen et at, 2000). 

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