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. 2003 Mar;111(3):255–261. doi: 10.1289/ehp.5785

Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase.

Jürg A Zarn 1, Beat J Brüschweiler 1, Josef R Schlatter 1
PMCID: PMC1241380  PMID: 12611652

Abstract

Azole compounds play a key role as antifungals in agriculture and in human mycoses and as non-steroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women. This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha-demethylase is crucial for the production of meiosis-activating sterols, which recently were shown to modulate germ cell development in both sexes of mammals. Aromatase is responsible for the physiologic balance of androgens and estrogens. At high doses, azole fungicides and other azole compounds affect reproductive organs, fertility, and development in several species. These effects may be explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact, several azole compounds were shown to inhibit these enzymes in vitro, and there is also strong evidence for inhibiting activity in vivo. Furthermore, the specificity of the enzyme inhibition of several of these compounds is poor, both with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus other P450 enzymes including aromatase. To our knowledge, this is the first review on sterol 14-alpha-demethylase and aromatase as common targets of azole compounds and the consequence for steroidogenesis. We conclude that many azole compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase with unknown potencies. For human health risk assessment, data on comparative potencies of azole fungicides to fungal and human enzymes are needed.

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Selected References

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  1. Andersen Helle Raun, Vinggaard Anne Marie, Rasmussen Thomas Hoj, Gjermandsen Irene Marianne, Bonefeld-Jørgensen Eva Cecilie. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15;179(1):1–12. doi: 10.1006/taap.2001.9347. [DOI] [PubMed] [Google Scholar]
  2. Ankley Gerald T., Kahl Michael D., Jensen Kathleen M., Hornung Michael W., Korte Joseph J., Makynen Elizabeth A., Leino Richard L. Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas). Toxicol Sci. 2002 May;67(1):121–130. doi: 10.1093/toxsci/67.1.121. [DOI] [PubMed] [Google Scholar]
  3. Belaid B., Richard-Mercier N., Pieau C., Dorizzi M. Sex reversal and aromatase in the European pond turtle: treatment with letrozole after the thermosensitive period for sex determination. J Exp Zool. 2001 Sep 15;290(5):490–497. doi: 10.1002/jez.1092. [DOI] [PubMed] [Google Scholar]
  4. Bhatnagar A. S., Brodie A. M., Long B. J., Evans D. B., Miller W. R. Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors. J Steroid Biochem Mol Biol. 2001 Jan-Mar;76(1-5):199–202. doi: 10.1016/s0960-0760(01)00050-4. [DOI] [PubMed] [Google Scholar]
  5. Bisagni G., Cocconi G., Scaglione F., Fraschini F., Pfister C., Trunet P. F. Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann Oncol. 1996 Jan;7(1):99–102. doi: 10.1093/oxfordjournals.annonc.a010490. [DOI] [PubMed] [Google Scholar]
  6. Bodey G. P. Azole antifungal agents. Clin Infect Dis. 1992 Mar;14 (Suppl 1):S161–S169. doi: 10.1093/clinids/14.supplement_1.s161. [DOI] [PubMed] [Google Scholar]
  7. Burke W. H., Henry M. H. Gonadal development and growth of chickens and turkeys hatched from eggs injected with an aromatase inhibitor. Poult Sci. 1999 Jul;78(7):1019–1033. doi: 10.1093/ps/78.7.1019. [DOI] [PubMed] [Google Scholar]
  8. Byskov A. G., Andersen C. Y., Nordholm L., Thøgersen H., Xia G., Wassmann O., Andersen J. V., Guddal E., Roed T. Chemical structure of sterols that activate oocyte meiosis. Nature. 1995 Apr 6;374(6522):559–562. doi: 10.1038/374559a0. [DOI] [PubMed] [Google Scholar]
  9. Byskov Anne Grete, Andersen Claus Yding, Leonardsen Lise. Role of meiosis activating sterols, MAS, in induced oocyte maturation. Mol Cell Endocrinol. 2002 Feb 22;187(1-2):189–196. doi: 10.1016/s0303-7207(01)00707-9. [DOI] [PubMed] [Google Scholar]
  10. Cavilla J. L., Kennedy C. R., Baltsen M., Klentzeris L. D., Byskov A. G., Hartshorne G. M. The effects of meiosis activating sterol on in-vitro maturation and fertilization of human oocytes from stimulated and unstimulated ovaries. Hum Reprod. 2001 Mar;16(3):547–555. doi: 10.1093/humrep/16.3.547. [DOI] [PubMed] [Google Scholar]
  11. Conley A., Hinshelwood M. Mammalian aromatases. Reproduction. 2001 May;121(5):685–695. doi: 10.1530/rep.0.1210685. [DOI] [PubMed] [Google Scholar]
  12. De Coster R., Van Ginckel R., Wouters W., Goeminne N., Vanherck W., Byloos M. Endocrine and antitumoral effects of R76713 in rats. J Enzyme Inhib. 1990;4(2):159–167. doi: 10.3109/14756369009040738. [DOI] [PubMed] [Google Scholar]
  13. Debeljak N., Horvat S., Vouk K., Lee M., Rozman D. Characterization of the mouse lanosterol 14alpha-demethylase (CYP51), a new member of the evolutionarily most conserved cytochrome P450 family. Arch Biochem Biophys. 2000 Jul 1;379(1):37–45. doi: 10.1006/abbi.2000.1859. [DOI] [PubMed] [Google Scholar]
  14. Dixon J. M., Renshaw L., Bellamy C., Stuart M., Hoctin-Boes G., Miller W. R. The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study. Clin Cancer Res. 2000 Jun;6(6):2229–2235. [PubMed] [Google Scholar]
  15. Downs S. M., Ruan B., Schroepfer G. J., Jr Meiosis-activating sterol and the maturation of isolated mouse oocytes. Biol Reprod. 2001 Jan;64(1):80–89. doi: 10.1095/biolreprod64.1.80. [DOI] [PubMed] [Google Scholar]
  16. Espinel-Ingroff A. Clinical relevance of antifungal resistance. Infect Dis Clin North Am. 1997 Dec;11(4):929–944. doi: 10.1016/s0891-5520(05)70398-6. [DOI] [PubMed] [Google Scholar]
  17. Evans C. T., Ledesma D. B., Schulz T. Z., Simpson E. R., Mendelson C. R. Isolation and characterization of a complementary DNA specific for human aromatase-system cytochrome P-450 mRNA. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6387–6391. doi: 10.1073/pnas.83.17.6387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fisher C. R., Graves K. H., Parlow A. F., Simpson E. R. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6965–6970. doi: 10.1073/pnas.95.12.6965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Foidart A., Harada N., Balthazart J. Effects of steroidal and non steroidal aromatase inhibitors on sexual behavior and aromatase-immunoreactive cells and fibers in the quail brain. Brain Res. 1994 Sep 19;657(1-2):105–123. doi: 10.1016/0006-8993(94)90958-x. [DOI] [PubMed] [Google Scholar]
  20. Fowler K. A., Gill K., Kirma N., Dillehay D. L., Tekmal R. R. Overexpression of aromatase leads to development of testicular leydig cell tumors : an in vivo model for hormone-mediated TesticularCancer. Am J Pathol. 2000 Jan;156(1):347–353. doi: 10.1016/S0002-9440(10)64736-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Georgopapadakou N. H. Antifungals: mechanism of action and resistance, established and novel drugs. Curr Opin Microbiol. 1998 Oct;1(5):547–557. doi: 10.1016/s1369-5274(98)80087-8. [DOI] [PubMed] [Google Scholar]
  22. Hickey G. J., Krasnow J. S., Beattie W. G., Richards J. S. Aromatase cytochrome P450 in rat ovarian granulosa cells before and after luteinization: adenosine 3',5'-monophosphate-dependent and independent regulation. Cloning and sequencing of rat aromatase cDNA and 5' genomic DNA. Mol Endocrinol. 1990 Jan;4(1):3–12. doi: 10.1210/mend-4-1-3. [DOI] [PubMed] [Google Scholar]
  23. Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001 Nov;45(11):2987–2990. doi: 10.1128/AAC.45.11.2987-2990.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jeong H. J., Shin Y. G., Kim I. H., Pezzuto J. M. Inhibition of aromatase activity by flavonoids. Arch Pharm Res. 1999 Jun;22(3):309–312. doi: 10.1007/BF02976369. [DOI] [PubMed] [Google Scholar]
  25. Ji H., Zhang W., Zhou Y., Zhang M., Zhu J., Song Y., Lü J. A three-dimensional model of lanosterol 14alpha-demethylase of Candida albicans and its interaction with azole antifungals. J Med Chem. 2000 Jun 29;43(13):2493–2505. doi: 10.1021/jm990589g. [DOI] [PubMed] [Google Scholar]
  26. Joseph-Horne T., Hollomon D. W. Molecular mechanisms of azole resistance in fungi. FEMS Microbiol Lett. 1997 Apr 15;149(2):141–149. doi: 10.1111/j.1574-6968.1997.tb10321.x. [DOI] [PubMed] [Google Scholar]
  27. Junker Walker U., Nogués V. Changes induced by treatment with aromatase inhibitors in testicular Leydig cells of rats and dogs. Exp Toxicol Pathol. 1994 Aug;46(3):211–213. doi: 10.1016/s0940-2993(11)80083-7. [DOI] [PubMed] [Google Scholar]
  28. Kojima M., Morozumi T., Onishi A., Mitsuhashi T. Structure of the pig sterol 14alpha-demethylase (CYP51) gene and its expression in the testis and other tissues. J Biochem. 2000 May;127(5):805–811. doi: 10.1093/oxfordjournals.jbchem.a022673. [DOI] [PubMed] [Google Scholar]
  29. Lamb D. C., Cannieux M., Warrilow A. G., Bak S., Kahn R. A., Manning N. J., Kelly D. E., Kelly S. L. Plant sterol 14 alpha-demethylase affinity for azole fungicides. Biochem Biophys Res Commun. 2001 Jun 15;284(3):845–849. doi: 10.1006/bbrc.2001.5010. [DOI] [PubMed] [Google Scholar]
  30. Lamb D. C., Kelly D. E., Waterman M. R., Stromstedt M., Rozman D., Kelly S. L. Characteristics of the heterologously expressed human lanosterol 14alpha-demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified human and Candida albicans CYP51 with azole antifungal agents. Yeast. 1999 Jun 30;15(9):755–763. doi: 10.1002/(SICI)1097-0061(19990630)15:9<755::AID-YEA417>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  31. Lee K., Macaulay V. M., Nicholls J. E., Detre S., Ashworth A., Dowsett M. An in vivo model of intratumoural aromatase using aromatase-transfected MCF7 human breast cancer cells. Int J Cancer. 1995 Jul 28;62(3):297–302. doi: 10.1002/ijc.2910620311. [DOI] [PubMed] [Google Scholar]
  32. Leonardsen L., Strömstedt M., Jacobsen D., Kristensen K. S., Baltsen M., Andersen C. Y., Byskov A. G. Effect of inhibition of sterol delta 14-reductase on accumulation of meiosis-activating sterol and meiotic resumption in cumulus-enclosed mouse oocytes in vitro. J Reprod Fertil. 2000 Jan;118(1):171–179. doi: 10.1530/jrf.0.1180171. [DOI] [PubMed] [Google Scholar]
  33. Lindenthal B., Holleran A. L., Aldaghlas T. A., Ruan B., Schroepfer G. J., Jr, Wilson W. K., Kelleher J. K. Progestins block cholesterol synthesis to produce meiosis-activating sterols. FASEB J. 2001 Mar;15(3):775–784. doi: 10.1096/fj.00-0214com. [DOI] [PubMed] [Google Scholar]
  34. Machera K. Developmental toxicity of cyproconazole, an inhibitor of fungal ergosterol biosynthesis, in the rat. Bull Environ Contam Toxicol. 1995 Mar;54(3):363–369. doi: 10.1007/BF00195106. [DOI] [PubMed] [Google Scholar]
  35. Majdic G., Parvinen M., Bellamine A., Harwood H. J., Jr, Ku W. W., Waterman M. R., Rozman D. Lanosterol 14alpha-demethylase (CYP51), NADPH-cytochrome P450 reductase and squalene synthase in spermatogenesis: late spermatids of the rat express proteins needed to synthesize follicular fluid meiosis activating sterol. J Endocrinol. 2000 Aug;166(2):463–474. doi: 10.1677/joe.0.1660463. [DOI] [PubMed] [Google Scholar]
  36. McPhaul M. J., Noble J. F., Matsumine H., Wilson J. D. Cloning and expression of the chicken ovary aromatase P-450: expression of mRNA in tissues of the Sebright and Leghorn chicken. Trans Assoc Am Physicians. 1988;101:219–225. [PubMed] [Google Scholar]
  37. McPherson S. J., Wang H., Jones M. E., Pedersen J., Iismaa T. P., Wreford N., Simpson E. R., Risbridger G. P. Elevated androgens and prolactin in aromatase-deficient mice cause enlargement, but not malignancy, of the prostate gland. Endocrinology. 2001 Jun;142(6):2458–2467. doi: 10.1210/endo.142.6.8079. [DOI] [PubMed] [Google Scholar]
  38. Means G. D., Mahendroo M. S., Corbin C. J., Mathis J. M., Powell F. E., Mendelson C. R., Simpson E. R. Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem. 1989 Nov 15;264(32):19385–19391. [PubMed] [Google Scholar]
  39. Menegola E., Broccia M. L., Di Renzo F., Giavini E. Antifungal triazoles induce malformations in vitro. Reprod Toxicol. 2001 Jul-Aug;15(4):421–427. doi: 10.1016/s0890-6238(01)00143-5. [DOI] [PubMed] [Google Scholar]
  40. Menegola E., Broccia M. L., Di Renzo F., Prati M., Giavini E. In vitro teratogenic potential of two antifungal triazoles: triadimefon and triadimenol. In Vitro Cell Dev Biol Anim. 2000 Feb;36(2):88–95. doi: 10.1290/1071-2690(2000)036<0088:IVTPOT>2.0.CO;2. [DOI] [PubMed] [Google Scholar]
  41. Middleton M. C., Milne C. M., Moreland S., Hasmall R. L. Ovulation in rats is delayed by a substituted triazole. Toxicol Appl Pharmacol. 1986 Apr;83(2):230–239. doi: 10.1016/0041-008x(86)90300-5. [DOI] [PubMed] [Google Scholar]
  42. Milne C. M., Hasmall R. L., Russell A., Watson S. C., Vaughan Z., Middleton M. C. Reduced estradiol production by a substituted triazole results in delayed ovulation in rats. Toxicol Appl Pharmacol. 1987 Sep 30;90(3):427–435. doi: 10.1016/0041-008x(87)90135-9. [DOI] [PubMed] [Google Scholar]
  43. Murray R. Role of anti-aromatase agents in postmenopausal advanced breast cancer. Cancer Chemother Pharmacol. 2001 Oct;48(4):259–265. doi: 10.1007/s002800100345. [DOI] [PubMed] [Google Scholar]
  44. Nitahara Y., Aoyama Y., Horiuchi T., Noshiro M., Yoshida Y. Purification and characterization of rat sterol 14-demethylase P450 (CYP51) expressed in Escherichia coli. J Biochem. 1999 Nov;126(5):927–933. doi: 10.1093/oxfordjournals.jbchem.a022536. [DOI] [PubMed] [Google Scholar]
  45. Odum J., Ashby John. Detection of aromatase inhibitors in vitro using rat ovary microsomes. Toxicol Lett. 2002 Mar 24;129(1-2):119–122. doi: 10.1016/s0378-4274(01)00521-5. [DOI] [PubMed] [Google Scholar]
  46. Podust L. M., Poulos T. L., Waterman M. R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3068–3073. doi: 10.1073/pnas.061562898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Raucy J. L., Carpenter S. J., Trzaskos J. M. Identification of lanosterol 14 alpha-methyl demethylase in human tissues. Biochem Biophys Res Commun. 1991 May 31;177(1):497–503. doi: 10.1016/0006-291x(91)92011-8. [DOI] [PubMed] [Google Scholar]
  48. Rissman E. F., Harada N., Roselli C. E. Effect of vorozole, an aromatase enzyme inhibitor, on sexual behavior, aromatase activity and neural immunoreactivity. J Neuroendocrinol. 1996 Mar;8(3):199–210. doi: 10.1046/j.1365-2826.1996.04505.x. [DOI] [PubMed] [Google Scholar]
  49. Robertson K. M., O'Donnell L., Jones M. E., Meachem S. J., Boon W. C., Fisher C. R., Graves K. H., McLachlan R. I., Simpson E. R. Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7986–7991. doi: 10.1073/pnas.96.14.7986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Robertson K. M., Simpson E. R., Lacham-Kaplan O., Jones M. E. Characterization of the fertility of male aromatase knockout mice. J Androl. 2001 Sep-Oct;22(5):825–830. [PubMed] [Google Scholar]
  51. Rozman D., Cotman M., Frangez R. Lanosterol 14alpha-demethylase and MAS sterols in mammalian gametogenesis. Mol Cell Endocrinol. 2002 Feb 22;187(1-2):179–187. doi: 10.1016/s0303-7207(01)00693-1. [DOI] [PubMed] [Google Scholar]
  52. Santen R. J., Harvey H. A. Use of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer. 1999 Mar;6(1):75–92. doi: 10.1677/erc.0.0060075. [DOI] [PubMed] [Google Scholar]
  53. Santner S. J., Pauley R. J., Tait L., Kaseta J., Santen R. J. Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocrinol Metab. 1997 Jan;82(1):200–208. doi: 10.1210/jcem.82.1.3672. [DOI] [PubMed] [Google Scholar]
  54. Schieweck K., Bhatnagar A. S., Batzl C., Lang M. Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):633–636. doi: 10.1016/0960-0760(93)90270-7. [DOI] [PubMed] [Google Scholar]
  55. Shetty G., Krishnamurthy H., Krishnamurthy H. N., Bhatnagar A. S., Moudgal N. R. Effect of long-term treatment with aromatase inhibitor on testicular function of adult male bonnet monkeys (M. radiata). Steroids. 1998 Jul-Aug;63(7-8):414–420. doi: 10.1016/s0039-128x(98)00042-7. [DOI] [PubMed] [Google Scholar]
  56. Shetty G., Krishnamurthy H., Krishnamurthy H. N., Bhatnagar S., Moudgal R. N. Effect of estrogen deprivation on the reproductive physiology of male and female primates. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):157–166. [PubMed] [Google Scholar]
  57. Shyadehi A. Z., Lamb D. C., Kelly S. L., Kelly D. E., Schunck W. H., Wright J. N., Corina D., Akhtar M. The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant sterol 14 alpha-demethylase of Candida albicans (other names are: lanosterol 14 alpha-demethylase, P-45014DM, and CYP51). J Biol Chem. 1996 May 24;271(21):12445–12450. doi: 10.1074/jbc.271.21.12445. [DOI] [PubMed] [Google Scholar]
  58. Sinha S., Kaseta J., Santner S. J., Demers L. M., Bremmer W. J., Santen R. J. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res Treat. 1998 Mar;48(1):45–51. doi: 10.1023/a:1005937900788. [DOI] [PubMed] [Google Scholar]
  59. Strömstedt M., Rozman D., Waterman M. R. The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Arch Biochem Biophys. 1996 May 1;329(1):73–81. doi: 10.1006/abbi.1996.0193. [DOI] [PubMed] [Google Scholar]
  60. Strömstedt M., Waterman M. R., Haugen T. B., Taskén K., Parvinen M., Rozman D. Elevated expression of lanosterol 14alpha-demethylase (CYP51) and the synthesis of oocyte meiosis-activating sterols in postmeiotic germ cells of male rats. Endocrinology. 1998 May;139(5):2314–2321. doi: 10.1210/endo.139.5.5984. [DOI] [PubMed] [Google Scholar]
  61. Tacer K. Fon, Haugen T. B., Baltsen M., Debeljak N., Rozman Damjana. Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS). J Lipid Res. 2002 Jan;43(1):82–89. [PubMed] [Google Scholar]
  62. Takayama K., Zeitoun K., Gunby R. T., Sasano H., Carr B. R., Bulun S. E. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril. 1998 Apr;69(4):709–713. doi: 10.1016/s0015-0282(98)00022-3. [DOI] [PubMed] [Google Scholar]
  63. Tanaka M., Telecky T. M., Fukada S., Adachi S., Chen S., Nagahama Y. Cloning and sequence analysis of the cDNA encoding P-450 aromatase (P450arom) from a rainbow trout (Oncorhynchus mykiss) ovary; relationship between the amount of P450arom mRNA and the production of oestradiol-17 beta in the ovary. J Mol Endocrinol. 1992 Feb;8(1):53–61. doi: 10.1677/jme.0.0080053. [DOI] [PubMed] [Google Scholar]
  64. Toda K., Shizuta Y. Molecular cloning of a cDNA showing alternative splicing of the 5'-untranslated sequence of mRNA for human aromatase P-450. Eur J Biochem. 1993 Apr 1;213(1):383–389. doi: 10.1111/j.1432-1033.1993.tb17772.x. [DOI] [PubMed] [Google Scholar]
  65. Toma Y., Higashiyama T., Yarborough C., Osawa Y. Diverse functions of aromatase: O-deethylation of 7-ethoxycoumarin. Endocrinology. 1996 Sep;137(9):3791–3796. doi: 10.1210/endo.137.9.8756548. [DOI] [PubMed] [Google Scholar]
  66. Trant J. M. Isolation and characterization of the cDNA encoding the channel catfish (Ictalurus punctatus) form of cytochrome P450arom. Gen Comp Endocrinol. 1994 Aug;95(2):155–168. doi: 10.1006/gcen.1994.1113. [DOI] [PubMed] [Google Scholar]
  67. Trzaskos J. M., Henry M. J. Comparative effects of the azole-based fungicide flusilazole on yeast and mammalian lanosterol 14 alpha-methyl demethylase. Antimicrob Agents Chemother. 1989 Aug;33(8):1228–1231. doi: 10.1128/aac.33.8.1228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Tsafriri A., Popliker M., Nahum R., Beyth Y. Effects of ketoconazole on ovulatory changes in the rat: implications on the role of a meiosis-activating sterol. Mol Hum Reprod. 1998 May;4(5):483–489. doi: 10.1093/molehr/4.5.483. [DOI] [PubMed] [Google Scholar]
  69. Tsafriri Alex, Cao Xiumei, Vaknin Karen M., Popliker Malka. Is meiosis activating sterol (MAS) an obligatory mediator of meiotic resumption in mammals. Mol Cell Endocrinol. 2002 Feb 22;187(1-2):197–204. doi: 10.1016/s0303-7207(01)00685-2. [DOI] [PubMed] [Google Scholar]
  70. Tuman R. W., Morris D. M., Wallace N. H., Bowden C. R. Inhibition of peripheral aromatization in the male cynomolgus monkey by a novel nonsteroidal aromatase inhibitor (R 76713). J Clin Endocrinol Metab. 1991 Apr;72(4):755–760. doi: 10.1210/jcem-72-4-755. [DOI] [PubMed] [Google Scholar]
  71. Vaknin K. M., Lazar S., Popliker M., Tsafriri A. Role of meiosis-activating sterols in rat oocyte maturation: effects of specific inhibitors and changes in the expression of lanosterol 14alpha-demethylase during the preovulatory period. Biol Reprod. 2001 Jan;64(1):299–309. doi: 10.1095/biolreprod64.1.299. [DOI] [PubMed] [Google Scholar]
  72. Vanderschueren D., van Herck E., Nijs J., Ederveen A. G., De Coster R., Bouillon R. Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats. Endocrinology. 1997 Jun;138(6):2301–2307. doi: 10.1210/endo.138.6.5216. [DOI] [PubMed] [Google Scholar]
  73. Vinggaard A. M., Hnida C., Breinholt V., Larsen J. C. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. Toxicol In Vitro. 2000 Jun;14(3):227–234. doi: 10.1016/s0887-2333(00)00018-7. [DOI] [PubMed] [Google Scholar]
  74. Wennstrom K. L., Crews D. Making males from females: the effects of aromatase inhibitors on a parthenogenetic species of whiptail lizard. Gen Comp Endocrinol. 1995 Sep;99(3):316–322. doi: 10.1006/gcen.1995.1115. [DOI] [PubMed] [Google Scholar]
  75. Wickman S., Sipilä I., Ankarberg-Lindgren C., Norjavaara E., Dunkel L. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet. 2001 Jun 2;357(9270):1743–1748. doi: 10.1016/S0140-6736(00)04895-9. [DOI] [PubMed] [Google Scholar]
  76. Yoshida Y., Aoyama Y. Interaction of azole antifungal agents with cytochrome P-45014DM purified from Saccharomyces cerevisiae microsomes. Biochem Pharmacol. 1987 Jan 15;36(2):229–235. doi: 10.1016/0006-2952(87)90694-0. [DOI] [PubMed] [Google Scholar]
  77. Zerulla Melanie, Länge R., Steger-Hartmann T., Panter G., Hutchinson T., Dietrich D. R. Morphological sex reversal upon short-term exposure to endocrine modulators in juvenile fathead minnow (Pimephales promelas). Toxicol Lett. 2002 May 10;131(1-2):51–63. doi: 10.1016/s0378-4274(02)00070-x. [DOI] [PubMed] [Google Scholar]
  78. Zhang Wenjiang, Ramamoorthy Yamini, Kilicarslan Tansel, Nolte Helma, Tyndale Rachel F., Sellers Edward M. Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos. 2002 Mar;30(3):314–318. doi: 10.1124/dmd.30.3.314. [DOI] [PubMed] [Google Scholar]
  79. de Jong P. C., van de Ven J., Nortier H. W., Maitimu-Smeele I., Donker T. H., Thijssen J. H., Slee P. H., Blankenstein R. A. Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third-generation aromatase inhibitor vorozole. Cancer Res. 1997 Jun 1;57(11):2109–2111. [PubMed] [Google Scholar]

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