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. 1993 Feb;67(2):284–289. doi: 10.1038/bjc.1993.54

Cortisol is transported by the multidrug resistance gene product P-glycoprotein.

C K van Kalken 1, H J Broxterman 1, H M Pinedo 1, N Feller 1, H Dekker 1, J Lankelma 1, G Giaccone 1
PMCID: PMC1968171  PMID: 8094292

Abstract

The physiology of the multidrug transporter P-glycoprotein (Pgp) is still poorly understood. We now show evidence that cell lines with a high expression of Pgp display a reduced accumulation of cortisol and an ATP-dependent outward transport of the hormone. Cortisol efflux from Pgp negative cells does not have such an active component. Further we show that the steroid hormones cortisol, testosterone, and progesterone cause an immediate, dose-dependent increase of daunorubicin accumulation in Pgp overexpressing cells. These effects are particularly apparent for the more lipophilic steroids. These results demonstrate that Pgp may function as a transporter for cortisol and suggest a physiological role of the protein in steroid handling by organs such as the adrenal.

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Selected References

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  1. Arceci R. J., Baas F., Raponi R., Horwitz S. B., Housman D., Croop J. M. Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol Reprod Dev. 1990 Feb;25(2):101–109. doi: 10.1002/mrd.1080250202. [DOI] [PubMed] [Google Scholar]
  2. Biedler J. L., Chang T. D., Scotto K. W., Melera P. W., Spengler B. A. Chromosomal organization of amplified genes in multidrug-resistant Chinese hamster cells. Cancer Res. 1988 Jun 1;48(11):3179–3187. [PubMed] [Google Scholar]
  3. Broxterman H. J., Pinedo H. M., Kuiper C. M., Kaptein L. C., Schuurhuis G. J., Lankelma J. Induction by verapamil of a rapid increase in ATP consumption in multidrug-resistant tumor cells. FASEB J. 1988 Apr;2(7):2278–2282. doi: 10.1096/fasebj.2.7.3350243. [DOI] [PubMed] [Google Scholar]
  4. Broxterman H. J., Pinedo H. M., Schuurhuis G. J., Lankelma J. Cyclosporin A and verapamil have different effects on energy metabolism in multidrug-resistant tumour cells. Br J Cancer. 1990 Jul;62(1):85–88. doi: 10.1038/bjc.1990.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen C. J., Chin J. E., Ueda K., Clark D. P., Pastan I., Gottesman M. M., Roninson I. B. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986 Nov 7;47(3):381–389. doi: 10.1016/0092-8674(86)90595-7. [DOI] [PubMed] [Google Scholar]
  6. Devine S. E., Hussain A., Davide J. P., Melera P. W. Full length and alternatively spliced pgp1 transcripts in multidrug-resistant Chinese hamster lung cells. J Biol Chem. 1991 Mar 5;266(7):4545–4555. [PubMed] [Google Scholar]
  7. Doody K. M., Carr B. R., Rainey W. E., Byrd W., Murry B. A., Strickler R. C., Thomas J. L., Mason J. I. 3 beta-hydroxysteroid dehydrogenase/isomerase in the fetal zone and neocortex of the human fetal adrenal gland. Endocrinology. 1990 May;126(5):2487–2492. doi: 10.1210/endo-126-5-2487. [DOI] [PubMed] [Google Scholar]
  8. Endicott J. A., Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171. doi: 10.1146/annurev.bi.58.070189.001033. [DOI] [PubMed] [Google Scholar]
  9. Fojo A. T., Ueda K., Slamon D. J., Poplack D. G., Gottesman M. M., Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A. 1987 Jan;84(1):265–269. doi: 10.1073/pnas.84.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Giorgi E. P., Stein W. D. The transport of steroids into animal cells in culture. Endocrinology. 1981 Feb;108(2):688–697. doi: 10.1210/endo-108-2-688. [DOI] [PubMed] [Google Scholar]
  11. Gottesman M. M., Pastan I. Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol Sci. 1988 Feb;9(2):54–58. doi: 10.1016/0165-6147(88)90117-4. [DOI] [PubMed] [Google Scholar]
  12. Gross S. R., Aronow L., Pratt W. B. The outward transport of cortisol by mammalian cells in vitro. J Cell Biol. 1970 Jan;44(1):103–114. doi: 10.1083/jcb.44.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hammond J. R., Johnstone R. M., Gros P. Enhanced efflux of [3H]vinblastine from Chinese hamster ovary cells transfected with a full-length complementary DNA clone for the mdr1 gene. Cancer Res. 1989 Jul 15;49(14):3867–3871. [PubMed] [Google Scholar]
  14. Lankelma J., Spoelstra E. C., Dekker H., Broxterman H. J. Evidence for daunomycin efflux from multidrug-resistant 2780AD human ovarian carcinoma cells against a concentration gradient. Biochim Biophys Acta. 1990 Dec 10;1055(3):217–222. doi: 10.1016/0167-4889(90)90035-c. [DOI] [PubMed] [Google Scholar]
  15. Nelson H. P., Kuhn R. W., Deyman M. E., Jaffe R. B. Human fetal adrenal definitive and fetal zone metabolism of pregnenolone and corticosterone: alternate biosynthetic pathways and absence of detectable aldosterone synthesis. J Clin Endocrinol Metab. 1990 Mar;70(3):693–698. doi: 10.1210/jcem-70-3-693. [DOI] [PubMed] [Google Scholar]
  16. Qian X. D., Beck W. T. Progesterone photoaffinity labels P-glycoprotein in multidrug-resistant human leukemic lymphoblasts. J Biol Chem. 1990 Nov 5;265(31):18753–18756. [PubMed] [Google Scholar]
  17. Schuurhuis G. J., Pinedo H. M., Broxterman H. J., van Kalken C. K., Kuiper C. M., Lankelma J. Differential sensitivity of multi-drug-resistant and -sensitive cells to resistance-modifying agents and the relation with reversal of anthracycline resistance. Int J Cancer. 1990 Aug 15;46(2):330–336. doi: 10.1002/ijc.2910460232. [DOI] [PubMed] [Google Scholar]
  18. Spoelstra E. C., Dekker H., Schuurhuis G. J., Broxterman H. J., Lankelma J. P-glycoprotein drug efflux pump involved in the mechanisms of intrinsic drug resistance in various colon cancer cell lines. Evidence for a saturation of active daunorubicin transport. Biochem Pharmacol. 1991 Feb 1;41(3):349–359. doi: 10.1016/0006-2952(91)90531-9. [DOI] [PubMed] [Google Scholar]
  19. Sugawara I., Kataoka I., Morishita Y., Hamada H., Tsuruo T., Itoyama S., Mori S. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res. 1988 Apr 1;48(7):1926–1929. [PubMed] [Google Scholar]
  20. Sugawara I., Nakahama M., Hamada H., Tsuruo T., Mori S. Apparent stronger expression in the human adrenal cortex than in the human adrenal medulla of Mr 170,000-180,000 P-glycoprotein. Cancer Res. 1988 Aug 15;48(16):4611–4614. [PubMed] [Google Scholar]
  21. Versantvoort C. H., Broxterman H. J., Pinedo H. M., de Vries E. G., Feller N., Kuiper C. M., Lankelma J. Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression. Cancer Res. 1992 Jan 1;52(1):17–23. [PubMed] [Google Scholar]
  22. Yang C. P., Cohen D., Greenberger L. M., Hsu S. I., Horwitz S. B. Differential transport properties of two mdr gene products are distinguished by progesterone. J Biol Chem. 1990 Jun 25;265(18):10282–10288. [PubMed] [Google Scholar]
  23. Yang C. P., DePinho S. G., Greenberger L. M., Arceci R. J., Horwitz S. B. Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus. J Biol Chem. 1989 Jan 15;264(2):782–788. [PubMed] [Google Scholar]
  24. van der Valk P., van Kalken C. K., Ketelaars H., Broxterman H. J., Scheffer G., Kuiper C. M., Tsuruo T., Lankelma J., Meijer C. J., Pinedo H. M. Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues. Analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol. 1990;1(1):56–64. [PubMed] [Google Scholar]

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