Cellular homeostasis requires the regulated entry and exit of a multitude of compounds across the cell’s plasma membrane. Cells must take up specific amounts of nutrients, metabolic precursors, inorganic ions, signaling molecules, and other macromolecules, while also exporting signaling molecules, hormones, electrolytes, metabolic waste products and xenobiotics. These transport events are mediated to a large extent by specific proteins that allow for selective movement of molecules into and out of the cell in a highly dynamic and regulated fashion. Although many of the critical proteins involved in these transport processes have now been identified, many others remain to be identified and characterized.

       In this regard, in 2001 our laboratory used a functional expression cloning strategy to identify a novel heterodimeric transporter, which we termed the Organic Solute and Steroid Transporter-alpha and beta (Ostα-Ostβ). These findings provide the only example of the successful use of expression cloning to simultaneously identify two interacting gene products. Our studies to date of this transporter’s substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of our recently characterized Ostα-deficient mice suggest that Ostα-Ostβ is a major basolateral membrane bile acid transporter, and that it may thus contribute to intestinal absorption of dietary fats and vitamins, and to cholesterol, bile acid, and lipid homeostasis. Studies are currently underway to test these possibilities.

       Our laboratory has also identified and characterized transport proteins that are responsible for cellular export of the tripeptide glutathione (GSH), a major antioxidant and regulator of a multitude of cellular processes, including differentiation, proliferation, and apoptosis. The initial and regulated step in GSH turnover in all mammalian cells is its export across the plasma membrane; however, the transport systems that mediate GSH efflux remain poorly defined. We are currently employing a novel functional complementation model to search for human genes that are involved in GSH transport and homeostasis.

Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, Jackson-Lewis V, Javitch JA, Ballatori N, Przedborski S, Tieu K. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci U S A. 2009 May 12;106(19):8043-8048.

Ballatori N, Li N, Fang F, Boyer JL, Christian WV, Hammond CL. OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci. 2009 Jan 1;14:2829-2844. Review.

Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009 Mar;390(3):191-214. Review.

Madejczyk MS, Boyer JL, Ballatori N. Hepatic uptake and biliary excretion of manganese in the little skate, Leucoraja erinacea. Comp Biochem Physiol C Toxicol Pharmacol. 2009 May;149(4):566-571.

Marchan R, Hammond CL, Ballatori N. Multidrug resistance-associated protein 1 as a major mediator of basal and apoptotic glutathione release. Biochim Biophys Acta. 2008 Jun 21. [Epub ahead of print]

Ballatori N, Fang F, Christian WV, Li N, Hammond CL. Ost{alpha}-Ost{beta} is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G179-186.

Hwang JH, Parton A, Czechanski A, Ballatori N, Barnes D. Arachidonic acid-induced expression of the organic solute and steroid transporter-beta (Ost-beta) in a cartilaginous fish cell line. Comp Biochem Physiol C Toxicol Pharmacol. 2008 Jul;148(1):39-47

Aremu DA, Madejczyk MS, Ballatori N. N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure. Environ Health Perspect. 2008 Jan;116(1):26-31.

Li N, Cui Z, Fang F, Lee JY, Ballatori N. Heterodimerization, trafficking and membrane topology of the two proteins, Ost alpha and Ost beta, that constitute the organic solute and steroid transporter. Biochem J. 2007 Nov 1;407(3):363-372.

Cai SY, Xiong L, Wray CG, Ballatori N, Boyer JL. The farnesoid X receptor FXRalpha/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution. Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1400-1409.

Clarkson TW, Vyas JB, Ballatori N. Mechanisms of mercury disposition in the body. Am J Ind Med. 2007 Oct;50(10):757-764. Review.

Madejczyk MS, Aremu DA, Simmons-Willis TA, Clarkson TW, Ballatori N. Accelerated urinary excretion of methylmercury following administration of its antidote N-acetylcysteine requires Mrp2/Abcc2, the apical multidrug resistance-associated protein. J Pharmacol Exp Ther. 2007 Jul;322(1):378-384.>

Mahagita C, Grassl SM, Piyachaturawat P, Ballatori N. Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport. Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G271-278.

Cernichiari E, Myers GJ, Ballatori N, Zareba G, Vyas J, Clarkson T. 2007. The biological monitoring of prenatal exposure to methylmercury. Neurotoxicology. 2007 Sep;28(5):1015-1022

Hammond CL, Marchan R, Krance SM, Ballatori N. 2007. Glutathione export during apoptosis requires functional multidrug resistance-associated proteins. J Biol Chem. 2007 May 11;282(19):14337-47.

Tradtrantip L, Piyachaturawat P, Soroka C, Harry K, Mennone A, Mahagita C, Ballatori N, Boyer JL. 2007. Phloracetophenone-Induced Choleresis in Rats is Mediated Through Mrp2. Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G66-74

Meier-Abt F, Hammann-Hanni A, Stieger B, Ballatori N, Boyer JL. 2007. The organic anion transport polypeptide 1d1 (Oatp1d1) mediates hepatocellular uptake of phalloidin and microcystin into skate liver. Toxicol Appl Pharmacol. Feb 1;218(3):274-279.