Cellular Localization of the Multidrug-resistance Gene Product P-glycoprotein in Normal Human Tissues

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1987 Nov 1

PMID 2444983

Citations 631

Authors

F Thiebaut

T Tsuruo

H Hamada

M M Gottesman

I Pastan

M C Willingham

Affiliations

Soon will be listed here.

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.

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References

Fojo A, Akiyama S, Gottesman M, Pastan I . Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res. 1985; 45(7):3002-7. View

Riordan J, Ling V . Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J Biol Chem. 1979; 254(24):12701-5. View

Wittes R, Goldin A . Unresolved issues in combination chemotherapy. Cancer Treat Rep. 1986; 70(1):105-25. View

Shen D, Fojo A, Chin J, Roninson I, Richert N, Pastan I . Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science. 1986; 232(4750):643-5. DOI: 10.1126/science.3457471. View

Scotto K, Biedler J, Melera P . Amplification and expression of genes associated with multidrug resistance in mammalian cells. Science. 1986; 232(4751):751-5. DOI: 10.1126/science.2421411. View

Roninson I, Chin J, Choi K, Gros P, Housman D, Fojo A . Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci U S A. 1986; 83(12):4538-42. PMC: 323769. DOI: 10.1073/pnas.83.12.4538. View

Willingham M, Cornwell M, Cardarelli C, Gottesman M, Pastan I . Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. Cancer Res. 1986; 46(11):5941-6. View

Hamada H, Tsuruo T . Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. Proc Natl Acad Sci U S A. 1986; 83(20):7785-9. PMC: 386806. DOI: 10.1073/pnas.83.20.7785. View

Ferro-Luzzi Ames G . The basis of multidrug resistance in mammalian cells: homology with bacterial transport. Cell. 1986; 47(3):323-4. DOI: 10.1016/0092-8674(86)90585-4. View

10.

Gros P, Croop J, Housman D . Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell. 1986; 47(3):371-80. DOI: 10.1016/0092-8674(86)90594-5. View

11.

Chen C, Chin J, Ueda K, Clark D, Pastan I, Gottesman M . Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986; 47(3):381-9. DOI: 10.1016/0092-8674(86)90595-7. View

12.

van der Bliek A, van der Velde-Koerts T, Ling V, Borst P . Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line. Mol Cell Biol. 1986; 6(5):1671-8. PMC: 367694. DOI: 10.1128/mcb.6.5.1671-1678.1986. View

13.

Gerlach J, Endicott J, Juranka P, Henderson G, Sarangi F, Deuchars K . Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature. 1986; 324(6096):485-9. DOI: 10.1038/324485a0. View

14.

Shen D, Fojo A, Roninson I, Chin J, Soffir R, Pastan I . Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene. Mol Cell Biol. 1986; 6(11):4039-45. PMC: 367169. DOI: 10.1128/mcb.6.11.4039-4045.1986. View

15.

Fojo A, Ueda K, Slamon D, Poplack D, Gottesman M, Pastan I . Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A. 1987; 84(1):265-9. PMC: 304184. DOI: 10.1073/pnas.84.1.265. View

16.

Pastan I, Gottesman M . Multiple-drug resistance in human cancer. N Engl J Med. 1987; 316(22):1388-93. DOI: 10.1056/NEJM198705283162207. View

17.

Ueda K, Cardarelli C, Gottesman M, Pastan I . Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci U S A. 1987; 84(9):3004-8. PMC: 304789. DOI: 10.1073/pnas.84.9.3004. View

18.

Fitzgerald D, Willingham M, Cardarelli C, Hamada H, Tsuruo T, Gottesman M . A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc Natl Acad Sci U S A. 1987; 84(12):4288-92. PMC: 305070. DOI: 10.1073/pnas.84.12.4288. View

19.

Kartner N, Bradley G, Ling V . Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature. 1985; 316(6031):820-3. DOI: 10.1038/316820a0. View