Progesterone-dependent and -independent expression of the multidrug resistance type I gene in porcine granulosa cells
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A primary role of plasma membrane P-glycoprotein (P-gp), encoded by multidrug resistance type I (MDR1), is to protect against naturally occurring xenotoxics. Progesterone (P4) profoundly influences MDR1 expression in granulosa cells and luteal cells. Here, P4 regulation of MDR1 expression was investigated in porcine granulosa cells using the P4-mediated promoter activity assay and a P4 receptor (PR) antagonist (RU-486). The promoter activity was measured chronologically for 48 h in cells transfected with the PR response element-containing pGL3. LH could stimulate the promoter activity through endogenous P4, with a maximum activity at 5 h. MDR1 mRNA level was highly maintained at 24–36 h. Conversely, exogenous P4 prolonged the promoter activity to further 10 h, and the high level of MDR1 mRNA was maintained even at 48 h. RU-486 completely inhibited the promoter activity, but the level of MDR1 mRNA rapidly increased in the presence of RU-486. The granulosa cells may become susceptible to RU-486 as a xenotoxic to rapidly express MDR1 for protection against it. These results indicate that MDR1 is expressed in porcine granulosa cells through P4-dependent and -independent regulations.
KeywordsMDR1 expression Progesterone RU-486 Granulosa cells Promoter activity
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This work was supported in part by a Grant-in-Aid for Scientific Research (B) No. 16380200 from the Japanese Ministry of Education, Culture, Sports, Science and Technology (to M-A H).
- 5.Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94:4028–4033PubMedCrossRefGoogle Scholar
- 7.Arboix M, Paz OG, Colombo T, D’Incalci M (1997) Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis. J Pharm Exp Ther 281:1226–1230Google Scholar
- 9.Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB (2000) Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Disp 28:655–660Google Scholar
- 21.He P-J, Fujimoto Y, Yamauchi N, Hattori M-A (2006) Real time monitoring of cAMP response element binding protein signaling in porcine granulosa cells modulated by ovarian factors. Mol Cell Biochem [in press]Google Scholar
- 23.Pickarz RL, Cohen D, Horwitz SB (1993) Progesterone regulates the murine multidrug resistance mdr1b gene. J Biol Chem 268:7613–7616Google Scholar