Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simultaneous exposure of lab animals to toxic doses of the human carcinogen arsenic (As) and the essential trace element selenium (Se) results in a remarkable mutual detoxification. A likely basis for this is the in vivo formation and biliary excretion of seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-); however, the transport protein responsible for the biliary efflux of [(GS)(2)AsSe](-) has not been identified. The multidrug resistance protein 2 (MRP2/ABCC2) is an adenosine triphosphate (ATP)-binding cassette transporter expressed at the canalicular membrane of hepatocytes. Rat Mrp2 is known to excrete the As glutathione (GSH/GS-) conjugates arsenic triglutathione [As(GS)(3)] and monomethyl arsenic diglutathione [CH(3)As(GS)(2)] into bile, and in vitro studies have established As(GS)(3) as a substrate for human MRP2. In the present study, membrane vesicles prepared from human embryonic kidney (HEK293T) cells transfected with human MRP2 were used to demonstrate that MRP2 transports [(GS)(2)AsSe](-). In addition, the characteristics of MRP2 transport of As(GS)(3) and [(GS)(2)AsSe](-) were investigated. As(GS)(3) and [(GS)(2)AsSe](-) are chemically labile and have the potential to dissociate. However, arsenite (As(III)) +/- selenite (Se(IV)) transport was not detected in the absence of GSH or in the presence of the non-reducing GSH analog, ophthalmic acid, suggesting that the conjugates are the transported forms. The apparent K(m) values for [(GS)(2)AsSe](-) and As(GS)(3) were 1.7 and 4.2 microM, respectively, signifying high relative affinities. Membrane vesicles prepared from human erythrocytes, which express the MRP2-related MRP1/ABCC1, MRP4/ABCC4 and MRP5/ABCC5, transported As(GS)(3) in an MRP1- and ATP-dependent manner but did not transport [(GS)(2)AsSe](-). These results have important implications for the Se-dependent and -independent disposition of As.
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PMID:Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium. 2058 51

Arsenic is the most toxic metalloid present in the natural environment in both organic and inorganic arsenic forms. Inorganic arsenic is often more hazardous than the organic form. Arsenite and arsenate compounds are the major inorganic forms which are toxic causing severe human health dysfunction including cancer. Excretion of arsenic from the system is found elusive. Therefore, it is of interest to screen channel proteins with the arsenic complex in the different combination of arsenic, GSH (glutathione) and arsenic, selenium using docking methods. The mode of arsenic removal. The complex structure revealed the mode of arsenic binding efficiency with the receptor aquaporine 9 and ABCC1 channel protein. This provides insights to understand the mechanism of arsenic efflux. These inferences find application in the design, identification and development of novel nutracetucal or any other formulation useful in the balance of arsenic efflux.
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PMID:Comparative Molecular Docking Studies with ABCC1 and Aquaporin 9 in the Arsenite Complex Efflux. 2525 80

Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (AsIII) is also an effective chemotherapeutic agent. The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.
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PMID:Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. 3081 97

The construction of a functional drug delivery system to reverse the multidrug resistance (MDR) of bone tumors in cases of failed chemotherapy remains a challenge. Herein, we demonstrate a selenium-doped calcium phosphate (Se-CaP) biomineral with high biocompatibility, biodegradability and pH-sensitive drug release properties. Se-CaP may not only serve as an effective drug-carrier to enhance the uptake of doxorubicin (DOX), but may also synchronously induce caspases-mediated apoptosis of osteosarcoma by generating intracellular reactive oxygen species (ROS). Furthermore, in vitro and in vivo studies obviously demonstrate that Se-CaP can reverse the MDR of osteosarcoma by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (ABCB1 and ABCC1). Finally, DOX-loaded Se-CaP can significantly inhibit DOX-resistant MG63 (MG63/DXR) tumor growth in nude mice. Considering its biomimetic chemical properties, the Se-CaP biomineral, with the multiple functions mentioned above, could be a promising candidate for treating bone tumors with MDR characteristics.
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PMID:Selenium-doped calcium phosphate biomineral reverses multidrug resistance to enhance bone tumor chemotherapy. 3318 94