Animal cells and systems

The Korean Society for Integrative Biology (한국통합생물학회)
권호 표지

Effects of Azoles on the In vitro Follicular Steroidogenesis in Amphibians

  • Kim, An-Na (Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University) ;
  • Ahn, Ryun-Seop (Graduate School, Pochon CHA University) ;
  • Kwon, Hyuk-Bang (Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University)
  • Published : 2006.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Azoles are widely used antifungal agents, which inhibit the biosynthesis of fungal cell-membrane ergosterol. In this study, using an amphibian follicle culture system, the effects of azoles on follicular steroidogenesis in frogs were examined. Itraconazole (ICZ), clotrimazole (CTZ) and ketoconazole (KCZ) suppressed pregnenolone ($P_5$) production by the follicles ($ED_{50};\;0.04_{\mu}M,\;0.33_{\mu} M,\;and\;0.91_{\mu}M$, respectively) in response to frog pituitary homogenates (FPH). However, fluconazole (FCZ), miconazole (MCZ) and econazole (ECZ) were not effective in the suppression of $P_5$ production. Not all the azoles examined suppressed the conversion of exogenous $P_5$ to progesterone ($P_4$) (by $3{\beta}$- HSD) or $P_4$ to $17{\alpha}$-hydroxyprogesterone ($17{\alpha}$-OHP) (by $17{\alpha}$-hydroxylase), or androstenedione (AD) to testosterone (T) (by $17{\beta}$-HSD). In contrast, CTZ, MCZ and ECZ in medium partially suppressed the conversion of $17{\alpha}$-OHP to AD (by C17-20 lyase) ($ED_{50};\;0.25{\mu} M,\;4.5{\mu}M,\;and\;0.7{mu}M$, respectively) and CTZ, KCZ, ECZ and MCZ strongly suppressed the conversion of exogenous T to estradiol ($E_2$) (by aromatase) ($ED_{50};\;0.02{\mu}M,\;8{\mu}M,\;0.07{\mu}M,\;0.8{\mu}M$, respectively). These results demonstrated that some azole agents strongly suppress amphibian follicular steroidogenesis and particularly, P450scc and aromatase are more sensitive to azoles than other steroidogenic enzymes.

Keywords

References

  1. Ahn RS, Soh JM, and Kwon HB (1996) Roles of Theca and Granulosa cells in Follicular Steroidogenesis in Rana dybowskii. Korean J Zool 39: 273-281
  2. Ahn RS, Yoo MS, and Kwon HB (1999) Evidence for two-cell model of steroidogenesis in four species of amphibian. J Exp Zool 284: 91-99 https://doi.org/10.1002/(SICI)1097-010X(19990615)284:1<91::AID-JEZ12>3.0.CO;2-F
  3. Aoyama Y, Noshiro M, Gotoh O, Imaoka S, Funae Y, Kurosawa N, Horiuchi T, and Yoshida Y (1996) Sterol14-demethylase P450 (p45014DM) is one of the most ancient and conserved P450 species. J Biochem Tokyo, 119: 926-933 https://doi.org/10.1093/oxfordjournals.jbchem.a021331
  4. Bodey GP (1992) Azole antifungal agents. Clin Irifect Dis 14(suppl 1): S161-S169 https://doi.org/10.1093/clinids/14.Supplement_1.S161
  5. Conley A and Hinshelwood M (2001) Mammalian aromatases. Reproduction 121: 685-695 https://doi.org/10.1530/rep.0.1210685
  6. Espinel-Ingroff A (1997) Clinical relevance of antifungal resistance. Irifect Dis Clin North Am 11: 929-944 https://doi.org/10.1016/S0891-5520(05)70398-6
  7. Georgopapadakou NH (1998) Antifungals: mechanism of action and resistance, established and novel drugs. Curr Opin Microbiol 1: 547-557 https://doi.org/10.1016/S1369-5274(98)80087-8
  8. Joseph-Horne T and Hollomon DW (1997) Molecular mechanisms of azole resistance in fungi. FEMS Microbiol Lett 149: 141-149 https://doi.org/10.1111/j.1574-6968.1997.tb10321.x
  9. Kwon HB and Ahn RS (1994) Relative roles of theca and granulosa cells in ovarian follicular steroidogenesis in the amphibian, Rana nigromaculata. Gen Comp Endocrinol 94: 207-214 https://doi.org/10.1006/gcen.1994.1077
  10. Kwon HB, Ahn RS, Lee WK, Im WB, Lee CC, and Kim KJ (1993) Changes in the activities of steroidogenic enzymes during the development of ovarian follicles in Rana nigromaculata. Gen Comp Endocrinol 92: 225-232 https://doi.org/10.1006/gcen.1993.1158
  11. Kwon HB and Schuetz AW (1985) Dichotomous effects of forskolin on somatic and germ cell components of the ovarian follicle: Evidence of cAMP involvement in steroid production and action. J Exp Zool 236: 219-228 https://doi.org/10.1002/jez.1402360212
  12. Murray R (2001) Role of anti-aromatase agents in postmenopausal advanced breast cancer. Cancer Chemother Pharmacol 48: 259-65 https://doi.org/10.1007/s002800100345
  13. Payne AH, and Hakes DB (2004) Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endoc Rev 25: 947-970 https://doi.org/10.1210/er.2003-0030
  14. Pedro RRM, Maria ARH, and Joao C (2000) Polycyclic aromatic hydrocarbons inhibit in vitro ovarian steroidogenesis in the flounder. Aquatic Toxicol 48: 549-559 https://doi.org/10.1016/S0166-445X(99)00055-7
  15. Petrino T and Schuetz AW (1987) Cholesterol mediation of progesterone production and oocyte maturation in cultured amphibian (Rana pipiens) ovarian follicles. Bioi Reprod 36: 1219-1228 https://doi.org/10.1095/biolreprod36.5.1219
  16. Tsafriri A, Popliker M, Nahum R, and Beyth Y (1998) Effects of ketoconazole on ovulatory changes in the rat: implications on the role of a meiosis-activating sterol. Mol Hum Reprod 4: 483-489 https://doi.org/10.1093/molehr/4.5.483
  17. Walsh LP, McCormick C, Martin C, and Stocco DM (2000a) Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression. Environ Health Perspect 108: 769-76 https://doi.org/10.2307/3434731
  18. Walsh LP, Kuratko CN, and Stocco DM (2000b) Econazole and miconazole inhibit steroidogenesis and disrupt steroidogenic acute regulatory (StAR) protein expression post-transcriptionally. J Steroid Biochem Mol Bioi 75: 229-236 https://doi.org/10.1016/S0960-0760(00)00170-9
  19. Zarn JA, Brschweiler BJ, and Schlatter JR (2003) Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14a-demethylase and aromatase. Environ Health Perspect 111: 255-261 https://doi.org/10.1289/ehp.5785