Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport

Mahagita, Chitrawina; Grassl, Steven M.; Piyachaturawat, Pawinee; Ballatori, Nazzareno

doi:10.1152/ajpgi.00075.2007

Cited by 105 publications

(76 citation statements)

References 31 publications

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“…Although OATP (human)/Oatp (rat, mouse) proteins were initially reported to mediate this exchange transport (57,58,62), a recent study has suggested that GSH/OA Ϫ exchange is not mediated by this family of transporters (65,66). We have previously detected the presence of mRNA for 7 different members of the SLCO/OATP family of transporters in Jurkat cells (13).…”

Section: Discussionmentioning

confidence: 97%

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Franco

Panayiotidis²,

Cidlowski

2007

Journal of Biological Chemistry

240

193

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Changes in the intracellular redox environment of cells have been reported to be critical for the activation of apoptotic enzymes and the progression of programmed cell death. Glutathione (GSH) depletion is an early hallmark observed in apoptosis, and we have demonstrated that GSH efflux during death receptor-mediated apoptosis occurs via a GSH transporter. We now evaluate the relationship between GSH depletion, the generation of reactive oxygen species (ROS), and the progression of apoptosis. Simultaneous single cell analysis of changes in GSH content and ROS formation by multiparametric FACS revealed that loss of intracellular GSH was paralleled by the generation of different ROS including hydrogen peroxide, superoxide anion, hydroxyl radical, and lipid peroxides. However, inhibition of ROS formation by a variety of antioxidants showed that GSH loss was independent from the generation of ROS. Furthermore, GSH depletion was observed to be necessary for ROS generation. Interestingly, high extracellular thiol concentration (GSH and N-acetyl-cysteine) inhibited apoptosis, whereas, inhibition of ROS generation by other non-thiol antioxidants was ineffective in preventing cell death. Finally, GSH depletion was shown to be a necessary for the progression of apoptosis activated by both extrinsic and intrinsic signaling pathways. These results document a necessary and critical role for GSH loss in apoptosis and clearly uncouple for the first time GSH depletion from ROS formation.Apoptosis or programmed cell death is a ubiquitous, evolutionary conserved process. Under physiological conditions it is important not only in the turnover of cells in all tissues, but also during the normal development and senescence of the organism. Moreover, its deregulation has been observed to occur as either a cause or consequence of distinct pathologies (1, 2). For example, apoptosis mediated by Fas ligand (FasL) 3 receptor (Fas/CD95/Apo-1) activation is necessary for the immune system homeostasis because of its role in the rapid clearance of immunoreactive T cells maintaining the immune balance and reducing the risk of autoimmune diseases (3). Apoptosis is a highly organized process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations. Initial stages of apoptosis are characterized by reactive oxygen species (ROS) formation, changes in intracellular ionic homeostasis, cell shrinkage, loss of membrane lipid asymmetry, and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by activation of execution caspases and endonucleases, apoptotic body formation, and cell fragmentation (1, 4, 5). Apoptosis has been widely reported to be modulated by changes in the redox status of the cell; however, the precise mechanisms involved are still unclear (6, 7). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is involved in many cellular processes including antioxidant defense, drug det...

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Section: Discussionmentioning

confidence: 97%

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Franco

Panayiotidis²,

Cidlowski

2007

Journal of Biological Chemistry

240

193

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“…Moreover, a pH-driven transport of bile acids in these cells has also been reported (Marin et al, 2003). Although OATP1B3 has recently been suggested to be sensitive to activation by glutathione (Briz et al, 2006), this could not be confirmed by other authors (Mahagita et al, 2007). The reason for these controversial results may be due in part to the existence of artifactually induced acidification of local pH by addition of glutathione to insufficiently buffered media (Briz et al, 2006).…”

Section: Introductionmentioning

confidence: 94%

Further Characterization of the Electrogenicity and pH Sensitivity of the Human Organic Anion-Transporting Polypeptides OATP1B1 and OATP1B3

Martinez-Becerra

Briz²,

Romero³

et al. 2010

Mol Pharmacol

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Organic anion-transporting polypeptides (OATPs) are involved in the liver uptake of many endogenous and xenobiotic compounds, such as bile acids and drugs, respectively. Using Xenopus laevis oocytes and Chinese hamster ovary (CHO) cells expressing rat Oatp1a1, human OATP1B1, or OATP1B3, the sensitivity of these transporters to extracellular/intracellular pH (pHo/pHi) and changes in plasma membrane potential (⌬⌿) was investigated. In X. laevis oocytes, nonspecific plasma membrane permeability increased only at pHo below 4.5. Above this value, both using oocytes and CHO cells, extracellular acidification affected differently the specific transport of taurocholic acid (TCA) and estradiol 17␤-D-glucuronide (E 2 17␤G) by Oatp1a1 (stimulation), OATP1B1 (inhibition), and OATP1B3 (stimulation). Changes in substrate uptake in the presence of valinomycin (K ϩ -ionophore), carbonyl cyanide 3-chlorophenylhydrazone and nigericin (protonophores), and amiloride (Na ϩ /H ϩ -inhibitor) and cation replacement in the medium were studied with fluorescent probes for measuring substrate uptake (cholylglycyl amidofluorescein) and changes in pHi (SNARF-4F) and ⌬⌿ [DilC 1 (5)]. The results suggest that activity of these three carriers is sodium/potassium-independent and affected differently by changes in pHo and ⌬⌿: Oatp1a1 was confirmed to be an electroneutral anion exchanger, whereas the function of both OATP1B1 and OATP1B3 was markedly affected by the magnitude of ⌬⌿. Moreover, electrophysiological measurements revealed the existence of a net anion influx associated to OATP1B1/OATP1B3-mediated transport of TCA, E 2 17␤G, and estrone-3-sulfate. Furthermore, a leakage of Na ϩ through OATP1B1 and OATP1B3, which is not coupled to substrate transport, was found. In conclusion, these results suggest that OATP1B1 and OATP1B3 are electrogenic transporters whose activity may be strongly affected under circumstances of displacement of local pH.

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“…The organic anion transporting polypeptides (OATP) have also been proposed to mediate GSH efflux by a GSH/OA À exchange, 40 although recent studies have suggested that GSH/OA À exchange is not mediated by this family of transporters. 41 Thus, there is a strong possibility that GSH efflux is mediated by a different and still uncharacterized entity. Whether GSH is depleted by its efflux, intracellular oxidation, or conjugation seems to depend on the nature and dose of the apoptotic stimuli.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport

Cited by 105 publications

References 31 publications

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Further Characterization of the Electrogenicity and pH Sensitivity of the Human Organic Anion-Transporting Polypeptides OATP1B1 and OATP1B3

Apoptosis and glutathione: beyond an antioxidant

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