Multidrug resistance-associated protein: A protein distinct from P-glycoprotein involved in cytotoxic drug expulsion

Barrand, Margery A.; Bagrij, Tanya; Neo, Soek-Ying

doi:10.1016/s0306-3623(96)00284-4

Cited by 75 publications

(46 citation statements)

References 31 publications

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“…Reagents and Materials-Clonal pancreatic MIN6 (a gift from Dr. S. Seino, Chiba University, passage number [40][41][42][43][44][45][46][47][48][49][50] and INS-1 (a gift from Dr. C. Wollheim, University Medical Center, Geneva, passage number 60-80) ␤-cells were used. Mouse hepatocytes were obtained as described by others (26).…”

Section: Methodsmentioning

confidence: 99%

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Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Koshkin

Dai

Doucette

et al. 2008

Journal of Biological Chemistry

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Involvement of the mitochondrial permeability transition (MPT) pore in early stages of lipotoxic stress in the pancreatic ␤-cell lines MIN6 and INS-1 was the focus of this study. Both long term (indirect) and acute (direct) effects of fatty acid (FA) application on ␤-cell susceptibility to Ca 2؉ -induced MPT induction were examined using both permeabilized and intact ␤-cells. Long term exposure to moderate (i.e. below cytotoxic) levels of the saturated FA palmitate sensitized ␤-cell mitochondria to MPT induced by Ca 2؉ . Long term exposure to palmitate was significantly a more efficient inducer of MPT than the unsaturated FA oleate, although upon acute application both caused similar MPT activation. Application of antioxidants, inhibitors of the ceramide pathway, or modifiers of membrane fluidity did not protect ␤-cell mitochondria from FA exposure. However, significant protection was provided by co-application of the unsaturated FA oleate in a phosphatidylinositol 3-kinase-dependent manner. Characterization of MPT pore opening in response to moderate palmitate treatment revealed the opening of a unique form of MPT in ␤-cells as it encompassed features of both low and high conductance MPT states. Specifically, this MPT showed solute selectivity, characteristic of a low conductance MPT; however, it affected mitochondrial respiration and membrane potential in a way typical of a high conductance MPT. Activation of the full-size/high conductance form of MPT required application of high levels of FA that reduced growth and initiated apoptosis. These findings suggest that in the ␤-cell, MPTs can act as both initiators of cell death and as versatile modulators of cell metabolism, depending on the mode of the MPT pore induced. Mitochondrial permeability transition (MPT)2 is the calcium (Ca 2ϩ )-dependent opening of a nonspecific pore in the mitochondrial inner membrane in response to a variety of inducers and co-inducers, including inorganic phosphate (P i ), thiol oxidants, fatty acids (FA), and others. Opening of the "full-size" or "high conductance" MPT causes equilibration across the inner membrane of ions and all solutes up to 1.5 kDa, which induces mitochondrial swelling and the release of mitochondrial proteins capable of apoptosis activation (1-5). MPT can also operate in a more "limited size" or "low conductance" mode, which allows passage of only small ions across the inner mitochondrial membrane (6, 7). Because opening of the low conductance MPT does not allow passage of large molecules, but does allow the passage of small ions, mitochondrial ion gradients and energy production are affected. As such, it is thought that the low conductance MPT functions not to induce cell death but to aid in the fine regulation of cell metabolism (6). Extensive evidence documents the high conductance MPT as a cause of generalized mitochondrial dysfunction and cell death, and an important mechanism in disease pathologies such as hepatotoxicity (8), cardiac ischemia/reperfusion (9, 10), and neuronal injury (10, 11). In contrast,...

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Section: Methodsmentioning

confidence: 99%

“…Also, it has been demonstrated that anion transporters (MDR-related proteins) can also contribute to fluorescent probe extrusion. To control for this, probenecid, which has been shown to inhibit these anion transporters in ␤-cells (42,43) as well as in other tissues (40,44), was employed.…”

Section: Mitochondrial Membrane Potential (⌿ M ) and Ca 2ϩmentioning

confidence: 99%

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Koshkin

Dai

Doucette

et al. 2008

Journal of Biological Chemistry

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“…Pgp, which is encoded by the human MDR1 gene, is a well-known drug efflux pump whose overexpression has been mainly observed in human cancer being resistant to anticancer chemotherapy. 4,5 Moreover, another drug efflux pump, the multidrug resistance-associated protein (MRP), has also been demonstrated in many cancer cell lines without Pgp expression. 6 In fact, 6 MRP isoforms called MRP1, MRP2, MRP3, MRP4, MRP5 and MRP6 have been discovered not only in human cancer cell lines but also in healthy human tissues.…”

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confidence: 99%

Molecular and functional MDR1‐Pgp and MRPs expression in human glioblastoma multiforme cell lines

Declèves

Fajac

Lehmann-Che

et al. 2002

Intl Journal of Cancer

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“…MRP1 is a 190 kDa protein coded by the ABCC1 gene and located on the plasma membrane of both normal and malignant cells (175). Specifically, in a cell, MRP1 transports multiple organic anions (some glutathione conjugates) protecting against oxidative stress and is reliant on the intercellular glutathione levels for anthracycline transport (176)(177)(178) of drug relative to P-gp, potentially due to their dependence on glutathione metabolism (130,179).…”

Section: P-gpmentioning

confidence: 99%

Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review)

Krishnan

Jaiswal

Brown

et al. 2016

International Journal of Oncology

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Multidrug resistance-associated protein: A protein distinct from P-glycoprotein involved in cytotoxic drug expulsion

Cited by 75 publications

References 31 publications

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Molecular and functional MDR1‐Pgp and MRPs expression in human glioblastoma multiforme cell lines

Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review)

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