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Acta Biologica Hungarica

, Volume 61, Issue 3, pp 274–281 | Cite as

Determination of Rat 5α-Reductase Type 1 Isozyme Activity and Its Inhibition by Novel Steroidal Oxazolines

  • M. SzécsiEmail author
  • Dóra Ondré
  • I. Tóth
  • S. Magony
  • J. Wölfling
  • Gy. Schneider
  • J. Julesz
Article

Abstract

The 5α-reductase type 1 isozyme is a key enzyme in the metabolism of the androgen steroid hormones and inhibitors of this enzyme represent a new pharmacological treatment for several androgen dependent diseases. We developed a radiosubstrate in vitro incubation method for the determination of 5α-reductase type 1 activity using rat liver microsomes as an enzyme source. With this method we have studied the inhibiting activity of novel (5’S)-17ß-(4,5-dihydrooxazol-5-yl)androst-5-en-3-one compounds containing various derivatized phenyl substituents coupled to the exo-heterocyclic moiety. Tests revealed moderate inhibitory actions compared to finasteride, nevertheless, results provide interesting structure-activity relationship data.

Keywords

5α-reductase inhibitors exo-heterocyclic steroids rat liver finasteride 

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References

  1. 1.
    Andersson, S., Russell D. W. (1990) Structural and biochemical properties of cloned and expressed human and rat steroid 5α-reductases. Proc. Natl. Acad. Sci. USA 87, 3640–3644.CrossRefGoogle Scholar
  2. 2.
    Bhattacharyya, A. K., Wang, M., Rajagopalan, K., Taylor, M. F., Hiipakka, R., Liao, S., Collins D. C. (1999) Analysis of the steroid binding domain of rat steroid 5α-reductase (isozyme-1): the steroid D-ring binding domain of 5α-reductase. Steroids 64, 197–204.CrossRefGoogle Scholar
  3. 3.
    Chen, W., Thiboutot, D., Zouboulis C. C. (2002) Cutaneous androgen metabolism: basic research and clinical perspectives. J. Invest. Dermatol. 119, 992–1007.CrossRefGoogle Scholar
  4. 4.
    Farkash, Y., Soreq, H., Orly, J. (1988) Biosynthesis of catalytically active rat testosterone 5α-reductase in microinjected Xenopus oocytes: evidence for tissue-specific differences in translatable mRNA. Proc. Natl. Acad Sci. USA 85, 5824–5828.CrossRefGoogle Scholar
  5. 5.
    Gerst, C., Dalko, M., Pichaud, P., Galey, J. B., Buan, B., Bernard B. A. (2002) Type-1 steroid 5α-reductase is functionally active in the hair follicle as evidenced by new selective inhibitors of either type-1 or type-2 human steroid 5α-reductase. Exp. Dermatol. 11, 52–58.CrossRefGoogle Scholar
  6. 6.
    Harris, G., Azzolina, B., Baginsky, W., Cimis, G., Rasmusson, G. H., Tolman, R. L., Raetz, C. R., Ellsworth, K. (1992) Identification and selective inhibition of an isozyme of steroid 5α-reductase in human scalp. Proc. Natl. Acad. Sci. USA 89, 10787–10791.CrossRefGoogle Scholar
  7. 7.
    Hoffmann, R., Happle, R. (2000) Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment. Eur. J. Dermatol. 10, 410–417.PubMedGoogle Scholar
  8. 8.
    Issa, S., Schnabel, D., Feix, M., Wolf, L., Schaefer, H. E., Russell D. W. Schweikert, H. U. (2002) Human osteoblast-like cells express predominantly steroid 5α-reductase type 1. J. Clin. Endocrinol Metab. 87, 5401–5407.CrossRefGoogle Scholar
  9. 9.
    Jarman, M., Smith, H. J., Nicholls, P. J., Simons, C. (1998) Inhibitors of enzymes of androgen biosynthesis: cytochrome P45017α and 5α-steroid reductase. Nat. Prod. Rep. 15, 495–512.CrossRefGoogle Scholar
  10. 10.
    Kenny, B., Ballard, S., Blagg, J., Fox, D. (1997) Pharmacological options in the treatment of benign prostatic hyperplasia. J. Med Chem. 40, 1293–1315.CrossRefGoogle Scholar
  11. 11.
    Li, X., Singh, S. M., Labrie, F. (1995) Synthesis and in vitro activity of 17ß-(N-alkyl/arylformamido)-and 17ßbeta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5α-androstan-3-ones as inhibitors of human 5α-reductases and antagonists of the androgen receptor. J. Med Chem. 38, 1158–1173.CrossRefGoogle Scholar
  12. 12.
    Machetti, F., Guarna, A. (2002) Novel inhibitors of 5α-reductase. Expert. Opin. Ther. Patents 12, 201–215.CrossRefGoogle Scholar
  13. 13.
    Melcangi, R. C., Poletti, A., Cavarretta, I., Celotti, F., Colciago, A., Magnaghi, V., Motta, M., Negri-Cesi, P., Martini, L. (1998) The 5alpha-reductase in the central nervous system: expression and modes of control. J. Steroid Biochem. Mol. Biol. 65, 295–299.CrossRefGoogle Scholar
  14. 14.
    Münster, U., Hammer, S., Blume-Peytavi, U., Schäfer-Korting, M. (2003) Testosterone metabolism in human skin cells in vitro and its interaction with estradiol and dutasteride. Skin. Pharmacol. Appl Skin. Physiol. 16, 356–366.CrossRefGoogle Scholar
  15. 15.
    Normington, K., Russel D. W. (1992) Tissue distribution and kinetic characterisation of rat steroid 5α-reductase isoenzymes. J. Biol. Chem. 267, 19548–19554.PubMedGoogle Scholar
  16. 16.
    Occhiato, E. G., Guarna, A., Danza, G., Serio, M. (2004) Selective non-steroidal inhibitors of 5α-reductase type 1. J. Steroid Biochem. Mol. Biol. 88, 1–16.CrossRefGoogle Scholar
  17. 17.
    Ondré, D., Wöffling, J., Tóth, L., Szécsi, M., Julesz, J., Schneider, Gy. (2009) Stereoselective synthesis of some steroidal 2-oxazolines, as novel potential inhibitors of 17a-hydroxylase-C17,20-lyase. Steroids 74, 1025–1032.CrossRefGoogle Scholar
  18. 18.
    Robaire, B., Henderson N. A. (2006) Actions of 5α-reductase inhibitors on the epididymis. Mol Cell. Endocrinol. 250, 190–195.CrossRefGoogle Scholar
  19. 19.
    Russel, D. W., Wilson J. D. (1994) Steroid 5α-reductase: two genes/two enzymes. Ann. Rev. Biochem. 65, 25–61.CrossRefGoogle Scholar
  20. 20.
    Salem, O. I., Frotscher, M., Scherer, C., Neugebauer, A., Biemel, K., Streiber, M., Maas, R., Hartmann R. W. (2006) Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids. J. Med. Chem. 49, 748–759.CrossRefGoogle Scholar
  21. 21.
    Steers, W. D. (2001) 5α-reductase activity in the prostate. Urology 58, 17–24.CrossRefGoogle Scholar
  22. 22.
    Sun, Z. Y., Xie, H., Tu Z. H. (1999) Effect of Finasteride and Epristeride on steroid 5α-reductase kinetics - a comparative in vitro study. Ind. J. Pharmacol. 31, 120–123.Google Scholar
  23. 23.
    Sun, Z. Y., Zheng, W. J., Feng, J., Tu Z. H. (1998) A convenient and rapid method to study enzymatic kinetics of steroid 5α-reductase inhibitors. Ind. J. Pharmacol. 30, 257–282.Google Scholar
  24. 24.
    Thigpen, A. E., Russell D. W. (1992) Four-amino acid segment in steroid 5α-reductase 1 confers sensitivity to finasteride, a competitive inhibitor. J. Biol. Chem. 267, 8577–8583.PubMedGoogle Scholar
  25. 25.
    Thigpen, A. E., Silver, R. I., Guileyardo, J. M., Casey, M. L., McConnell, J. D., Russell D. W. (1993) Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. J. Clin. Invest. 92, 903–910.CrossRefGoogle Scholar
  26. 26.
    Tian, G., Haffner C. D. (2001) Linear relationship between the ligand binding energy and the activation energy of time-dependent inhibition of steroid 5α-reductase by 1-4-azasteroids. J. Biol. Chem. 276, 21359–21364.CrossRefGoogle Scholar
  27. 27.
    Titus, M. A., Gregory, C. W., Ford O. H. 3rd, Schell, M. J., Maygarden, S. J., Mohler J. L. (2005) Steroid 5α-reductase isozymes I and II in recurrent prostate cancer. Clin. Cancer. Res. 11, 4365–4371.CrossRefGoogle Scholar
  28. 28.
    Torres, J. M., Ortega, E. (2003) Precise quantitation of 5α-reductase type 1 mRNA by RT-PCR in rat liver and its positive regulation by testosterone and dihydrotestosterone. Biochem. Biophys. Res. Commun. 308, 469–473.CrossRefGoogle Scholar
  29. 29.
    Torres, J. M., Ortega, E. (2004) Precise quantitation of steroid 5α-reductase type 1 mRNA levels by RT-PCR in female rat liver. Endocr. Res. 30, 149–157.CrossRefGoogle Scholar
  30. 30.
    Zhu, Y S., Imperato-McGinley, J. L. (2009) 5α-reductase isozymes and androgen actions in the prostate. Ann. N. Y. Acad. Sci. 1155, 43–56.CrossRefGoogle Scholar

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© Akadémiai Kiadó, Budapest 2010

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • M. Szécsi
    • 1
    Email author
  • Dóra Ondré
    • 2
  • I. Tóth
    • 1
  • S. Magony
    • 1
  • J. Wölfling
    • 2
  • Gy. Schneider
    • 2
  • J. Julesz
    • 1
  1. 1.1st Department of MedicineUniversity of SzegedSzegedHungary
  2. 2.Department of Organic ChemistryUniversity of SzegedSzegedHungary

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