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Mechanisms of Testosterone Effects on the Transport Protein P-Glycoprotein

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Abstract

P-glycoprotein (Pgp) is an efflux membrane transport protein that plays an important role in the protection of tumor cells from cytostatics and drug pharmacokinetics. Testosterone is known to be able to reduce Pgp activity and expression, but the mechanisms of its action remain unexplored. The aim of this study was to evaluate the mechanism underlying the effect of testosterone on Pgp functioning, specifically, the role of androgen (AR), pregnane X (PXR), and constitutive androstane (CAR) receptors in this mechanism both in vitro and in vivo. In in vitro experiments on Caco-2 cell line, testosterone (1 and 10 µM, 24 h) reduced the Pgp level (Western blotting) compared to the control. The PXR inhibitor ketoconazole (1 and 10 µM, 24 h) did not affect the Pgp level, while the CAR inhibitor CINPA (10 µM) reduced it. The combination of CINPA (10 µM) and testosterone (10 µM) also reduced the Pgp level, however, the latter was not significantly different from the values obtained with CINPA and testosterone applied individually. In in vivo experiments on male Chinchilla rabbits, single intramuscular injection of testosterone undecanoate (24 mg/kg b.w.) increased the serum testosterone level on day 21 compared to the control, whereas after orchiectomy, its content decreased on postoperative day 21. Relative Pgp and CAR levels in the rabbit jejunum decreased after testosterone injection and increased with orchiectomy. PXR and АR levels in the rabbit jejunum did not change significantly. Thus, both in vitro and in vivo experiments demonstrated that testosterone inhibits the CAR and thus reduces the level of the transport protein Pgp.

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REFERENCES

  1. Mollazadeh S, Sahebkar A, Hadizadeh F, Behravan J, Arabzadeh S (2018) Structural and functional aspects of P-glycoprotein and its inhibitors. Life Sci 214: 118–123. https://doi.org/10.1016/j.lfs.2018.10.048

    Article  CAS  PubMed  Google Scholar 

  2. Chin KV, Liu B (1994) Regulation of the multidrug resistance (MDR1) gene expression (Review). In Vivo 8(5): 835–841.

    CAS  PubMed  Google Scholar 

  3. Gessner A, König J, Fromm MF (2019) Clinical Aspects of Transporter-Mediated Drug-Drug Interactions. Clin Pharmacol Ther 105(6): 1386–1394. https://doi.org/10.1002/cpt.1360

    Article  CAS  PubMed  Google Scholar 

  4. Zhang J, Zhang M, Zhang J, Wang R (2020) Enhanced P-glycoprotein expression under high-altitude hypoxia contributes to increased phenytoin levels and reduced clearance in rats. Eur J Pharm Sci 1(153): 105490. https://doi.org/10.1016/j.ejps.2020.105490

    Article  CAS  Google Scholar 

  5. Shchulkin AV, Abalenikhina YV, Erokhina PD, Chernykh IV, Yakusheva EN (2021) The Role of P-Glycoprotein in Decreasing Cell Membranes Permeability during Oxidative Stress. Biochemistry (Mosc) 86(2): 197–206. https://doi.org/10.1134/S0006297921020085

  6. Shchulkin AV, Yakusheva EN, Popova NM (2013) The role of glycoprotein-P in rational pharmacotherapy in cardiology. Rational Pharmacother Cardiol 9(6): 701–707. https://doi.org/10.20996/1819-6446-2013-9-6-701-707

    Article  Google Scholar 

  7. Erokhina PD, Abalenikhina YuV, Shchulkin AV, Chernykh IV, Popova NM, Slepnev AA, Yakusheva EN (2020) A study of influence of progesterone on activity of glycoprotein-P in vitro. IPPavlov Rus Med Biol Herald 28(2): 135–142. https://doi.org/10.23888/PAVLOVJ2020282135-142

    Article  Google Scholar 

  8. Zhang H, Xu H, Ashby ChR, Assaraf YG, Chen Zh, Liu H (2021) Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp). Med Res Rev 41 (1): 525–555. https://doi.org/10.1002/med.21739

    Article  CAS  PubMed  Google Scholar 

  9. Dey S, Gunda S, Mitra AK (2004) Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption. J Pharmacol Exp Therap311 (1): 246–255. https://doi.org/10.1124/jpet.104.069583

    Article  CAS  Google Scholar 

  10. Van Kalken CK, Broxterman HJ, Pinedo HM, Feller N, Dekker H, Lankelma J, Giaccone G (1993) Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br J Cancer 67(2): 284–289. https://doi.org/10.1038/bjc.1993.54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang CP, DePinho SG, Greenberger LM, Arceci RJ, Horwitz SB (1989) Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus. J Biol Chem 264: 782–788.

    Article  CAS  PubMed  Google Scholar 

  12. Nakayama A, Eguchi O, Hatakeyama M, Saitoh H, Takada M (1999) Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat small intestine. Biol Pharm Bull 22: 535–538. https://doi.org/10.1248/bpb.22.535

    Article  CAS  PubMed  Google Scholar 

  13. Suzuki T, Zhao YL, Nadai M, Naruhashi K, Shimizu A, Takagi K, Takagi K, Hasegawa T (2006) Gender-related differences in expression and function of hepatic P-glycoprotein and multidrug resistance-associated protein (Mrp2) in rats. Life Sci 79(5): 455–461. https://doi.org/10.1016/j.lfs.2006.01.024

    Article  CAS  PubMed  Google Scholar 

  14. Shchulkin AV, Yakusheva EN, Chernykh IV, Nikiforov AA (2017) The role of testosterone in the regulation of P-glycoprotein functioning. Biol Bull 44: 524–530. https://doi.org/10.1134/S1062359017050168

    Article  CAS  Google Scholar 

  15. Shchulkin AV, Yakusheva EN, Chernykh IV, Nikiforov AA, Popova NM (2017) Effects of testosterone on the functional activity of P-glycoprotein. Pharm Chem J 51(9): 743–747. https://doi.org/10.1007/s11094-017-1685-1

    Article  CAS  Google Scholar 

  16. Hilgers AR, Conradi RA, Burton PS (1990) Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharmac Res 7 (9): 902–910. https://doi.org/10.1023/a:1015937605100

    Article  CAS  Google Scholar 

  17. Fuchs I, Hafner-Blumenstiel V, Markert C, Burhenne J, Weiss J, Haefeli W E, Mikus G (2013) Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity. Eur J Clin Pharmacol 69 (3): 507–513. https://doi.org/10.1007/s00228-012-1388-1

    Article  CAS  PubMed  Google Scholar 

  18. Cherian MT, Lin W, Wu J, Chen T (2015) CINPA1 is an inhibitor of constitutive androstane receptor that does not activate pregnane X receptor. Mol Pharmacol 87 (5): 878–889. https://doi.org/10.1124/mol.115.097782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moore LB, Maglich JM, McKee DD, Wisely B, Willson TM, Kliewer SA, Lambert MH, Moore JT (2002) Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrin 16 (5): 977–986. https://doi.org/10.1210/mend.16.5.0828

    Article  CAS  Google Scholar 

  20. Gaczanoga MV, Chernykh IV, Shchulkin AV, Yakusheva EN, Popova NM (2016) Is it possible to assess the affiliation of medicinal substances to glycoprotein-P substrates on female chinchilla rabbits? Nauka molodykh (Eruditio Juvenium) 3: 5–10. (In Russ).

  21. Zhao C, Moon DG, Park JK (2013) Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. Can Urol Assoc J 7(3–4): 221–225. https://doi.org/10.5489/cuaj.507

    Article  Google Scholar 

  22. Razina AV, Frolova AI, Sergeev MA (2010) Optimization of general anesthesia on rabbits. Akt Vopr Veterinarii i Biol 1: 32–35. (In Russ).

    Google Scholar 

  23. Yakusheva EN, Chernykh IV, Shchulkin AV, Popova NM (2014) Glycoprotein-P: structure, physiological role and molecular mechanisms of functional activity modulation. Usp fiziol nauk 45(4): 89–98. (In Russ).

    Google Scholar 

  24. Buchman CD, Chai SC, Chen TA (2018) Current structural perspective on PXR and CAR in drug metabolism. Exp Opin Drug Metab Toxicol 14(6): 635–647. https://doi.org/10.1080/17425255.2018.1476488

    Article  CAS  Google Scholar 

  25. Burk O, Kuzikov M, Kronenberger T, Jeske J, Keminer O, Thasler WE, Schwab M, Wrenger C, Windshugel B (2018) Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. Arch Toxicol 92(4): 1435–1451. https://doi.org/10.1007/s00204-018-2165-4

    Article  CAS  PubMed  Google Scholar 

  26. Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA (2011) Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology 285(1-2): 18–24. https://doi.org/10.1016/j.tox.2011.03.015

    Article  CAS  PubMed  Google Scholar 

  27. Slosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente ML, Vanderah TW, Ronaldson PT, Davis TP (2013) Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 84(5): 774–786. https://doi.org/10.1124/mol.113.086298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, Moore DD (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395: 612–615. https://doi.org/10.1038/26996

    Article  CAS  PubMed  Google Scholar 

  29. Kawamoto T, Kakizaki S, Yoshinari K, Negishi M (2000) Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene. Mol Endocrinol 14(11): 1897–1905. https://doi.org/10.1210/mend.14.11.0547

    Article  CAS  PubMed  Google Scholar 

  30. Chan GNY, Hoque T, Cummins CL, Bendayan R (2011) Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J Neurochem 118 (2): 163–175. https://doi.org/10.1111/j.1471-4159.2011.07288.x

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Russian Foundation for Basic Research (FRBR), grants nos. 18-415-623001 and 16-04-00320.

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Authors and Affiliations

  1. Ryazan State Medical University, Ryazan, Russia

    A. A. Slepnev, A. V. Shchulkin, Yu. V. Abalenikhina, N. M. Popova, I. V. Chernykh & E. N. Yakusheva

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  1. A. A. Slepnev
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  2. A. V. Shchulkin
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  3. Yu. V. Abalenikhina
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  4. N. M. Popova
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  5. I. V. Chernykh
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  6. E. N. Yakusheva
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Contributions

Conceptualization and experimental design (A.V.Sh., E.N.Ya.); data collection (Yu.V.A., N.M.P.); data processing (A.A.S.); writing and editing of the manuscript (A.V.Sh., E.N.Ya.).

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Correspondence to Yu. V. Abalenikhina.

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The authors declare that they have neither evident nor potential conflict of interest related to the publication of this article.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 9, pp. 1188–1199https://doi.org/10.31857/S0869813922090059.

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Slepnev, A.A., Shchulkin, A.V., Abalenikhina, Y.V. et al. Mechanisms of Testosterone Effects on the Transport Protein P-Glycoprotein. J Evol Biochem Phys 58, 1514–1522 (2022). https://doi.org/10.1134/S0022093022050210

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