The UV-filter benzophenone-1 inhibits 17β-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals

Biochemical Pharmacology

Volumn 79, Issue 8, 2010, Pages 1189-1199

  Nashev, Lyubomir G ^a   Schuster, Daniela ^b   Laggner, Christian ^b   Sodha, Seloni ^a   Langer, Thierry ^c   Wolber, Gerhard ^b,d   Odermatt, Alex ^a  

^a UNIVERSITY OF BASEL   (Switzerland)

^b UNIVERSITY OF INNSBRUCK   (Austria)

^c Prestwick Chemical Inc   (France)

^d Inte:Ligand GmbH   (Austria)

Author keywords

17 Hydroxysteroid dehydrogenase; Androgen; Endocrine disruptor; Pharmacophore; Testosterone; UV filter; Virtual screening

Indexed keywords

3 (4 METHYLBENZYLIDENE)CAMPHOR; ANDROGEN; ANDROGEN RECEPTOR; ANDROSTENEDIONE; BENZOPHENONE; CINNAMIC ACID DERIVATIVE; DIOXYBENZONE; ENDOCRINE DISRUPTOR; ESTROGEN; TESTOSTERONE; TESTOSTERONE 17BETA DEHYDROGENASE;

ANDROGEN METABOLISM; ANIMAL TISSUE; ARTICLE; CHEMICAL ANALYSIS; CHEMICAL STRUCTURE; CONTROLLED STUDY; EMBRYO; ENZYME ASSAY; ENZYME INHIBITION; ENZYME MECHANISM; ESTROGEN METABOLISM; HUMAN; HUMAN CELL; LEYDIG CELL; MOUSE; NONHUMAN; PHARMACOPHORE; PRIORITY JOURNAL; RAT; RECEPTOR UPREGULATION; REFERENCE DATABASE; SAFETY; SCREENING TEST; SEXUAL DEVELOPMENT; TESTOSTERONE SYNTHESIS; ULTRAVIOLET RADIATION;

17-HYDROXYSTEROID DEHYDROGENASES; ANIMALS; BENZOPHENONES; DATABASES, FACTUAL; ENDOCRINE DISRUPTORS; ENZYME INHIBITORS; MALE; MICE; RATS; RECEPTORS, ANDROGEN; STRUCTURE-ACTIVITY RELATIONSHIP; TESTIS; TESTOSTERONE;

EID: 77249113148     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2009.12.005     Document Type: Article

References (62)

1. Travison T.G., Araujo A.B., O'Donnell A.B., Kupelian V., McKinlay J.B. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab 2007, 92:196-202.
2. Sharpe R.M., Skakkebaek N.E. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril 2008, 89:e33-e38.
3. Huyghe E., Matsuda T., Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003, 170:5-11.
4. Cummings A.M., Kavlock R.J. Function of sexual glands and mechanism of sex differentiation. J Toxicol Sci 2004, 29:167-178.
5. Parks L.G., Ostby J.S., Lambright C.R., Abbott B.D., Klinefelter G.R., Barlow N.J., et al. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 2000, 58:339-349.
6. Mahood I.K., Hallmark N., McKinnell C., Walker M., Fisher J.S., Sharpe R.M. Abnormal Leydig cell aggregation in the fetal testis of rats exposed to di (n-butyl) phthalate and its possible role in testicular dysgenesis. Endocrinology 2005, 146:613-623.
7. Egnatz D.G., Ott M.G., Townsend J.C., Olson R.D., Johns D.B. DBCP and testicular effects in chemical workers: an epidemiological survey in Midland, Michigan. J Occup Med 1980, 22:727-732.
8. Mylchreest E., Sar M., Cattley R.C., Foster P.M. Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol 1999, 156:81-95.
9. Singleton D.W., Khan S.A. Xenoestrogen exposure and mechanisms of endocrine disruption. Front Biosci 2003, 8:s110-s118.
10. Guillette L.J. Endocrine disrupting contaminants-beyond the dogma. Environ Health Perspect 2006, 114(Suppl. 1):9-12.
11. Wang C.Y., Ai N., Arora S., Erenrich E., Nagarajan K., Zauhar R., et al. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chem Res Toxicol 2006, 19:1595-1601.
12. Devillers J., Marchand-Geneste N., Dore J.C., Porcher J.M., Poroikov V. Endocrine disruption profile analysis of 11,416 chemicals from chemometrical tools. SAR QSAR Environ Res 2007, 18:181-193.
13. Jacobs M.N. In silico tools to aid risk assessment of endocrine disrupting chemicals. Toxicology 2004, 205:43-53.
14. Geissler W.M., Davis D.L., Wu L., Bradshaw K.D., Patel S., Mendonca B.B., et al. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Nat Genet 1994, 7:34-39.
15. Andersson S., Geissler W.M., Wu L., Davis D.L., Grumbach M.M., New M.I., et al. Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab 1996, 81:130-136.
16. Boehmer A.L., Brinkmann A.O., Sandkuijl L.A., Halley D.J., Niermeijer M.F., Andersson S., et al. 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 1999, 84:4713-4721.
17. Lo S., Allera A., Albers P., Heimbrecht J., Jantzen E., Klingmuller D., et al. Dithioerythritol (DTE) prevents inhibitory effects of triphenyltin (TPT) on the key enzymes of the human sex steroid hormone metabolism. J Steroid Biochem Mol Biol 2003, 84:569-576.
18. Ohno S., Nakajima Y., Nakajin S. Triphenyltin and tributyltin inhibit pig testicular 17beta-hydroxysteroid dehydrogenase activity and suppress testicular testosterone biosynthesis. Steroids 2005, 70:645-651.
19. EPA Priority setting database 2001, Available: http://wwwepagov/scipoly/oscpendo/pubs/prioritysetting/database.htm [accessed 17 May 2009].
20. Rosania G.R., Crippen G., Woolf P., States D., Shedden K. A cheminformatic toolkit for mining biomedical knowledge. Pharm Res 2007, 24:1791-1802.
21. Wheeler D.L., Barrett T., Benson D.A., Bryant S.H., Canese K., Chetvernin V., et al. Database resources of the national center for biotechnology information. Nucleic Acids Res 2008, 36:D13-21.
22. NCBI. PubChem Substance database, National Center for Biotechnology Information, National Institutes of Health. Available: [accessed 17 July 2007]. ftp://ftpncbinlmnihgov/pubchem/Substance/.
23. IUPAC The IUPAC international chemical identifier (InChI™) 2006, Available: www.iupac.org/inchi/ [accessed 17 May 2009].
24. Stein S.E., Heller S.R., Tchekhovski D An open standard for chemical structure representation-the IUPAC chemical identifier. Nimes International Chemical Information Conference Proceedings 2003, 131-143. Nimes, France.
25. Ma R., Cotton B., Lichtensteiger W., Schlumpf M. UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay. Toxicol Sci 2003, 74:43-50.
26. Schreurs R.H., Sonneveld E., Jansen J.H., Seinen W., van der Burg B. Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays. Toxicol Sci 2005, 83:264-272.
27. Kunz P.Y., Fent K. Estrogenic activity of UV filter mixtures. Toxicol Appl Pharmacol 2006, 217:86-99.
28. Heneweer M., Muusse M., van den Berg M., Sanderson J.T. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol 2005, 208:170-177.
29. Okereke C.S., Abdel-Rhaman M.S., Friedman M.A. Disposition of benzophenone-3 after dermal administration in male rats. Toxicol Lett 1994, 73:113-122.
30. Pelletier G., Luu-The V., El-Alfy M., Li S., Labrie F. Immunoelectron microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary gland. J Mol Endocrinol 2001, 26:11-19.
31. Luu-The V. Analysis and characteristics of multiple types of human 17beta-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 2001, 76:143-151.
32. Nokelainen P., Puranen T., Peltoketo H., Orava M., Vihko P., Vihko R. Molecular cloning of mouse 17 beta-hydroxysteroid dehydrogenase type 1 and characterization of enzyme activity. Eur J Biochem/FEBS 1996, 236:482-490.
33. EU Regulation (EC) No 1907/2006 of the European Parliament and of the Council 2006, OJEU, pp. 1-849.
34. CORDIS Can household chemicals affect your fertility? 2008, Available: cordis.europa.eu/search/index.cfm?fuseaction=news.document&N_RCN=29543 [accessed 20 May 2009].
35. Doman T.N., McGovern S.L., Witherbee B.J., Kasten T.P., Kurumbail R., Stallings W.C., et al. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem 2002, 45:2213-2221.
36. Molina-Molina J.M., Escande A., Pillon A., Gomez E., Pakdel F., Cavailles V., et al. Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays. Toxicol Appl Pharmacol 2008, 232:384-395.
37. Silva E., Rajapakse N., Kortenkamp A. Something from " nothing" -eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 2002, 36:1751-1756.
38. Kunz P.Y., Fent K. Multiple hormonal activities of UV filters and comparison of in vivo and in vitro estrogenic activity of ethyl-4-aminobenzoate in fish. Aquat Toxicol (Amsterdam, Netherlands) 2006, 79:305-324.
39. Mindnich R., Moller G., Adamski J. The role of 17 beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 2004, 218:7-20.
40. Oduwole O.O., Makinen M.J., Isomaa V.V., Pulkka A., Jernvall P., Karttunen T.J., et al. 17Beta-hydroxysteroid dehydrogenase type 2: independent prognostic significance and evidence of estrogen protection in female patients with colon cancer. J Steroid Biochem Mol Biol 2003, 87:133-140.
41. Oliveira I.O., Lhullier C., Brum I.S., Spritzer P.M. Gene expression of type 2 17 beta hydroxysteroid dehydrogenase in scalp hairs of hirsute women. Steroids 2003, 68:641-649.
42. Poiger T., Buser H.R., Balmer M.E., Bergqvist P.A., Muller M.D. Occurrence of UV filter compounds from sunscreens in surface waters: regional mass balance in two Swiss lakes. Chemosphere 2004, 55:951-963.
43. Fent K. UV filters in the aquatic environment induce hormonal effects and affect fertility and reproduction in fish. Chimia 2008, 62:368-375.
44. Nagtegaal M., Ternes T.A., Baumann W., Nagel R. Detection of UV-sunscreen agents in water and fisch of the Meerfelder Maar in the Eifel Germany. UWSF-Z für Umweltchem Oekotox 1997, 9:79-86.
45. Balmer M.E., Buser H.R., Muller M.D., Poiger T. Occurrence of some organic UV filters in wastewater, in surface waters, and in fish from Swiss Lakes. Environ Sci Technol 2005, 39:953-962.
46. Klinubol P., Asawanonda P., Wanichwecharungruang S.P. Transdermal penetration of UV filters. Skin Pharmacol Physiol 2008, 21:23-29.
47. Janjua N.R., Mogensen B., Andersson A.M., Petersen J.H., Henriksen M., Skakkebaek N.E., et al. Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzylidene) camphor after whole-body topical application and reproductive hormone levels in humans. Journal Invest Dermatol 2004, 123:57-61.
48. Schlumpf M., Kypke K., Vökt C.C., Birchler M., Durrer S., Faass O., et al. Endocrine active UV filters: developmental toxicity and exposure through breast milk. Chimia 2008, 62:345-351.
49. Schlumpf M., Schmid P., Durrer S., Conscience M., Maerkel K., Henseler M., et al. Endocrine activity and developmental toxicity of cosmetic UV filters-an update. Toxicology 2004, 205:113-122.
50. Delemarre-van de Waal H.A., van Coeverden S.C., Engelbregt M.T. Factors affecting onset of puberty. Horm Res 2002, 57(Suppl. 2):15-18.
51. Janjua N.R., Kongshoj B., Andersson A.M., Wulf H.C. Sunscreens in human plasma and urine after repeated whole-body topical application. J Eur Acad Dermatol Venereol 2008, 22:456-461.
52. Wolff M.S., Engel S.M., Berkowitz G.S., Ye X., Silva M.J., Zhu C., et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect 2008, 116:1092-1097.
53. Wolber G., Dornhofer A., Langer T. Efficient overlay of small molecules using 3-D pharmacophores. J Comput Aided Mol Des 2006, 20:773-788.
54. Wolber G., Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 2005, 45:160-169.
55. Fink B.E., Gavai A.V., Tokarski J.S., Goyal B., Misra R., Xiao H.Y., et al. Identification of a novel series of tetrahydrodibenzazocines as inhibitors of 17beta-hydroxysteroid dehydrogenase type 3. Bioorg Med Chem Lett 2006, 16:1532-1536.
56. Maltais R., Luu-The V., Poirier D. Synthesis and optimization of a new family of type 3 17β-hydroxysteroid dehydrogenase inhibitors by parallel liquid-phase chemistry. J Med Chem 2002, 45:640-653.
57. Spires T.E., Fink B.E., Kick E.K., You D., Rizzo C.A., Takenaka I., et al. Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3). Prostate 2005, 65:159-170.
58. Tchedam Ngatcha B., Luu-The V., Labrie F., Poirier D. Androsterone 3alpha-ether-3beta-substituted and androsterone 3beta-substituted derivatives as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: chemical synthesis and structure-activity relationship. J Med Chem 2005, 48:5257-5268.
59. Maltais R., Luu-The V., Poirier D. Parallel solid-phase synthesis of 3β-peptido-3α-hydroxy-5α-androstan-17-one derivatives for inhibition of type 3 17β-hydroxysteroid dehydrogenase. Bioorg Med Chem 2001, 9:3101-3111.
60. Le Lain R., Barrell K.J., Saeed G.S., Nicholls P.J., Simons C., Kirby A., et al. Some coumarins and triphenylethene derivatives as inhibitors of human testes microsomal 17β-hydroxysteroid dehydrogenase (17β-HSD type 3): further studies with tamoxifen on the rat testes microsomal enzyme. J Enzyme Inhib Med Chem 2002, 17:93-100.
61. +) cells. J Enzyme Inhib Med Chem 2002, 17:155-165.
62. Poirier D., Labrie F., Merand Y., Luu-The V., Gauthier S., Belanger A., et al. Inhibitors of type 5 and type 3 17beta-hydroxysteroid dehydrogenase and methods for their use 1999, Marks & Clerk, Canada. E. Inc (Ed.).