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Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues
F Thiebaut1, T Tsuruo, H Hamada
1Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Abstract:
Monoclonal antibody MRK16 was used to determine the location of P-glycoprotein, the product of the multidrug-resistance gene (MDR1), in normal human tissues. The protein was found to be concentrated in a small number of specific sites. Most tissues examined revealed very little P-glycoprotein. However, certain cell types in liver, pancreas, kidney, colon, and jejunum showed specific localization of P-glycoprotein. In liver, P-glycoprotein was found exclusively on the biliary canalicular front of hepatocytes and on the apical surface of epithelial cells in small biliary ductules. In pancreas, P-glycoprotein was found on the apical surface of the epithelial cells of small ductules but not larger pancreatic ducts. In kidney, P-glycoprotein was found concentrated on the apical surface of epithelial cells of the proximal tubules. Colon and jejunum both showed high levels of P-glycoprotein on the apical surfaces of superficial columnar epithelial cells. Adrenal gland showed high levels of P-glycoprotein diffusely distributed on the surface of cells in both the cortex and medulla. These results suggest that the protein has a role in the normal secretion of metabolites and certain anti-cancer drugs into bile, urine, and directly into the lumen of the gastrointestinal tract.
Insights
P-glycoprotein (MDR1) is concentrated in specific human tissues, including the liver, kidney, and gut. This finding suggests its role in secreting metabolites and drugs.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- P-glycoprotein, encoded by the multidrug-resistance gene (MDR1), is a key transporter protein.
- Understanding its tissue distribution is crucial for drug disposition and toxicity studies.
Purpose of the Study:
- To map the precise localization of P-glycoprotein in normal human tissues.
- To elucidate the physiological role of P-glycoprotein in normal tissue function.
Main Methods:
- Utilized the monoclonal antibody MRK16 for immunohistochemical detection.
- Examined a range of normal human tissues including liver, pancreas, kidney, colon, jejunum, and adrenal gland.
Main Results:
- P-glycoprotein was found in high concentrations at specific cellular locations, primarily on apical surfaces.
- Significant localization observed in liver (biliary canaliculi), kidney (proximal tubules), colon/jejunum (epithelial cells), pancreas (ductules), and adrenal gland.
- Most other tissues showed minimal P-glycoprotein expression.
Conclusions:
- P-glycoprotein is strategically located in human tissues involved in secretion.
- Suggests a role in the physiological secretion of endogenous metabolites and xenobiotics, including anti-cancer drugs, into bile, urine, and the gastrointestinal tract.