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Tissue distribution of the multidrug resistance protein
M J Flens1, G J Zaman, P van der Valk
1Department of Pathology, Free University Hospital, Netherlands Cancer Institute, Amsterdam.
Abstract:
The human multidrug resistance protein (MRP) is a 190 kd membrane glycoprotein that can cause resistance of human tumor cells to various anticancer drugs, by extruding these drugs out of the cell. Three different monoclonal antibodies, directed against different domains of MRP, allowed us to determine the localization of MRP in a panel of normal human tissues and malignant tumors. Whereas in malignant tumors strong plasma membrane MRP staining was frequently observed, in normal human tissues MRP staining was predominantly cytoplasmatic. Here, MRP was detected in several types of epithelia, muscle cells, and macrophages. From the presence of MRP in many epithelia we infer that MRP, like MDR1 P-glycoprotein, may have an excretory function in protecting the organism against xenobiotics. Recent studies indicate a role for MRP as a carrier for transport of glutathione-conjugated endo- and xenobiotics. The presence of MRP in bronchiolar epithelium, heart muscle, and macrophages would agree with the glutathione S-conjugate carrier activity previously detected in these cells. Furthermore, in 46 of 119 untreated tumors from various histogenetic origins MRP staining was seen. In these tumors MRP may contribute to the intrinsic resistance against treatment with chemotherapeutic drugs.
Insights
The human multidrug resistance-associated protein (MRP) is found in the cytoplasm of normal tissues but on the plasma membrane of tumor cells. This localization suggests MRP
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- The human multidrug resistance-associated protein (MRP) is a 190 kDa membrane glycoprotein.
- MRP mediates resistance in human tumor cells to anticancer drugs by extruding them from the cell.
Purpose of the Study:
- To determine the localization of MRP in normal human tissues and malignant tumors.
- To investigate the potential excretory and xenobiotic transport functions of MRP.
Main Methods:
- Utilized three distinct monoclonal antibodies targeting different MRP domains.
- Performed immunohistochemical staining on a panel of normal human tissues and untreated tumors.
Main Results:
- In malignant tumors, strong plasma membrane MRP staining was frequently observed.
- In normal human tissues, MRP staining was predominantly cytoplasmic, detected in epithelia, muscle cells, and macrophages.
- MRP staining was present in 46 out of 119 untreated tumors.
Conclusions:
- MRP's differential localization suggests a role in protecting the organism against xenobiotics, similar to MDR1 P-glycoprotein.
- MRP's presence in specific tissues aligns with its proposed function as a carrier for glutathione-conjugated endo- and xenobiotics.
- MRP may contribute to the intrinsic drug resistance observed in various untreated tumors.