The multidrug resistance-associated protein (MRP) is over-expressed and functional in rat hepatoma cells

Payen, Léa; Courtois, Arnaud; Vernhet, Laurent; Fardel, Olivier

doi:10.1002/(sici)1097-0215(19990505)81:3<479::aid-ijc24>3.0.co;2-s

Cited by 22 publications

(2 citation statements)

References 27 publications

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“…As a result, tumor promotion and finally malignant progression may be accelerated. The biochemical basis for this phenomenon is an increase of metabolic pathways favoring inactivation and extrusion of toxic compounds, e.g., conjugation reactions by the GSTp and other GSH-transferases, or membrane transport by P-glycoprotein and MRP-family members (5,8,10,11,19,31,32,37). Also, in humans, resistance to cytotoxins seems to be important for hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Expression of the lung resistance-related protein in human and rat hepatocarcinogenesis

Raidl

Berger

Schulte‐Hermann

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Lung resistancerelated protein (LRP) plays an important role in chemoresistance of tumor cells probably by altering nuclear-cytoplasmic transport processes. We analyzed the association between LRP expression and hepatocarcinogenesis in humans and rats by RT-PCR, immunoblotting, and immunohistochemistry. LRP was found in hepatocytes and bile epithelia of normal human and rat liver showing distinct interindividual variations. In human tissues, the LRP expression levels of dysplastic liver nodules, hepatocellular adenomas, and carcinomas were highly variable, including decreased but also distinctly increased staining intensities. Mean expression levels, however, were comparable to the surrounding tissue. Considerable levels of LRP mRNA and protein were also found in human hepatoma cell lines. To study LRP expression from the beginning of hepatocarcinogenesis onward, rats were subjected to a tumor initiation/promotion protocol leading to preneoplastic hepatocytes present as single cells or multicellular clones, followed by adenoma and carcinoma. All of the (pre)neoplastic rat liver lesions expressed, comparable to the surrounding tissue, considerable amounts of LRP. We conclude that LRP might be one mechanism involved in the intrinsically high but variable chemoresistance of normal and (pre)neoplastic hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Expression of the lung resistance-related protein in human and rat hepatocarcinogenesis

Raidl

Berger

Schulte‐Hermann

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Gradual cell sensitisation is associated with the formation and cytoplasmatic accumulation of polyglutamated toxic derivative of methotrexate which is not a substrate for MRPs. The processes of drug transport outside the cell are accompanied by extensive GSH efflux from the cell [47]. The cells devoid of the ability to synthesise MRP show high glutathione levels in the cytoplasm due to accumulation [4].…”

Section: Glutathione Involvement In Transmembrane Transportmentioning

confidence: 99%

Role of Glutathione in the Multidrug Resistance in Cancer

Karwicka¹

2010

Advances in Cell Biology

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Summary: Multidrug resistance is the main problem in anticancer therapy. Cancer cells use many defense strategies in order to survive chemotherapy. Among known multidrug resistance mechanisms the most important are: drug detoxification inside the cell using II phase detoxifying enzymes and active transport of the drug to the extracellular environment. Cancer cells may be also less sensitive to proapoptotic signals and have different intracellular drug distribution, which makes them more resistant to anticancer drugs. Role of glutathione in multidrug resistance is the object of interest of many scientists, however, defining it's function in these processes still remains a challenge. In this paper, properties of glutathione and it's role in multidrug resistance in cancer cells were described.

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Functional expression of p-glycoprotein and multidrug resistance-associated protein (mrp1) in primary cultures of rat astrocytes

et al. 2000

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Although it has been well established that the drug efflux pump P-glycoprotein (P-gp) protects the brain against the entry of cytotoxic drugs, its real in situ localization, i.e., at brain capillary endothelial cells or on astrocyte foot processes, is still controversial. The aim of this study was to compare the expression of P-gp and of multidrug resistance-associated protein (Mrp1), another drug efflux pump, in cultured neonatal rat brain astrocytes and in cultured brain capillary endothelial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that the mdr1b gene was preferentially expressed in astrocytes, whereas both mdr1a and mdr1b mRNA were detected in endothelial cells. Moreover, the mrp1 gene encoding Mrp1 was expressed in both cell types. Western blotting analysis revealed higher expression of P-gp in endothelial cells as compared with astrocytes, but higher expression of Mrp1 in astrocytes. Moreover, P-gp and Mrp1 expression was not modified in more differentiated astrocytes obtained when cultured with db-cAMP for 48 hr. Our functional analysis of P-gp showed a modest effect of P-gp modulators (CsA, verapamil, PSC 833) on the uptake of colchicine (a substrate of P-gp) by astrocytes, whereas they increased by about 50% the uptake of vincristine (a common substrate of P-gp and MRP) by astrocytes. MRP modulators (genistein, probenecid, and sulfinpyrazone) did not modify the uptake of colchicine but increased that of vincristine with a major effect found for sulfinpyrazone. Moreover, indomethacin, probenecid, and sulfinpyrazone increased the uptake of fluorescein (a substrate of MRP but not of P-gp). Taken together, our results provide the first biochemical and functional evidence supporting the expression of P-gp and Mrp1 in rat cultured astrocytes.

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The multidrug resistance-associated protein (MRP) is over-expressed and functional in rat hepatoma cells

Cited by 22 publications

References 27 publications

Expression of the lung resistance-related protein in human and rat hepatocarcinogenesis

Expression of the lung resistance-related protein in human and rat hepatocarcinogenesis

Role of Glutathione in the Multidrug Resistance in Cancer

Functional expression of p-glycoprotein and multidrug resistance-associated protein (mrp1) in primary cultures of rat astrocytes

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