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DOI: 10.1055/s-2007-961814
© Georg Thieme Verlag KG Stuttgart · New York
Inhibition of 5α-Reductase Activity in SZ95 Sebocytes and HaCaT Keratinocytes In Vitro
Publikationsverlauf
received 5. 9. 2006
accepted 8. 11. 2006
Publikationsdatum:
27. Februar 2007 (online)
![](https://www.thieme-connect.de/media/hmr/200702/lookinside/thumbnails/10.1055-s-2007-961814-1.jpg)
Abstract
Inhibition of 5α-reductase type 1 has been considered to be a promising target for treatment of androgen-dependent skin disorders, however, currently published clinical results on acne treatment are rather disappointing. In this study, the influence of selective inhibitors of 5α-reductase on testosterone metabolism within SZ95 sebocytes and HaCaT keratinocytes in vitro was investigated. In both cell types, the isotype 1 inhibitor MK386 completely inhibited the conversion of testosterone to 5α-dihydrotestosterone in concentrations higher than 10-9 M. Inhibitors of the isotype 2 such as finasteride, dihydrofinasteride, and turosteride, were >100-fold less active, while, as expected, androgen receptor inhibitors did not affect the 5α-reductase activity. MK386, but not finasteride, reduced testosterone-stimulated proliferation and slightly reduced the testosterone-induced increase in the amount of SZ95 sebocyte proteins. The androgen receptor inhibitor cyproterone acetate exhibited no effect on testosterone-induced proliferation, but inhibited the 5α-dihydrotestosterone-induced sebocyte proliferation. Our experimental findings and the existing clinical results indicate that the inhibition of 5α-reductase activity alone may be insufficient to reduce overall sebocyte activity and improve acne lesions.
Keywords
androgens - anti-androgens - 5α-reductase inhibitors - sebaceous gland - keratinocytes - cell proliferation - acne
References
- 1 Chen W, Thiboutot D, Zouboulis CC. Cutaneous androgen metabolism - Basic research and clinical perspectives. J Invest Dermatol. 2002; 119 992-1007
- 2 Zouboulis CC, Degitz K. Androgen action on human skin - From basic research to clinical significance. Exp Dermatol. 2004; 13 ((Suppl 4)) 5-10
- 3 Sansone G, Reisner RM. Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin - a possible pathogenic factor in acne. J Invest Dermatol. 1971; 56 36-72
- 4 Chen W, Yang C-C, Sheu H-M, Seltmann H, Zouboulis CC. Expression of sex-determining genes in human sebaceous glands and their possible roles in pathogenesis of acne. J Eur Acad Dermatol Venereol. , in press
- 5 Chen W, Tsai S-J, Liao C-Y, Tsai R-Y, Chen Y-R, Pan B-J, Hung C-L, Zouboulis CC. Higher levels of steroidogenic acute regulatory protein and type I 3β-hydroxysteroid dehydrogenase in the scalp of men with androgenetic alopecia. J Invest Dermatol. 2006; 126 2332-2335
- 6 Thiboutot D, Harris G, Iles V, Cimis G, Guilliland H, Hagari S. Activity of the type 1 5alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol. 1995; 105 209-214
- 7 Chen W, Zouboulis CC, Fritsch M, Blume-Peytavi U, Kodelja V, Goerdt S, Luu-The V, Orfanos CE. Evidence of heterogeneity and quantitative differences of the type 1 5α-reductase expression in cultured human skin cells. Evidence of its presence in melanocytes. J Invest Dermatol. 1998; 110 84-89
- 8 Luu-The V, Sugimoto Y, Puy L, Labrie Y, Lopez Solache I, Singh M, Labrie F. Characterization, expression and immunohistochemical localization of 5 alpha-reductase in human skin. J Invest Dermatol. 1994; 102 221-226
- 9 Eicheler W, Dreher M, Hoffmann R, Happle R, Aumüller G. Immunohistochemical evidence for differential distribution of 5 alpha-reductase isoenzymes in human skin. Br J Dermatol. 1995; 133 371-376
- 10 Bayne EK, Flanagan J, Einstein M, Ayala J, Chang B, Azzolina B, Whiting DA, Mumford RA, Thiboutot D, Singer II, Harris G. Immunohistochemical localization of types 1 and 2 5α-reductase in human scalp. Br J Dermatol. 1999; 141 481-491
- 11 Thiboutot D, Bayne E, Thorne J, Gilliland K, Flanagan J, Shao Q, Light J, Helm K. Immunolocalization of 5alpha-reductase isozymes in acne lesions and normal skin. Arch Dermatol. 2000; 136 1125-1129
- 12 Fritsch M, Orfanos CE, Zouboulis CC. Sebocytes are the key regulators of androgen homeostasis in human skin. J Invest Dermatol. 2001; 116 793-800
- 13 Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, Heffernan MP, Hickman JG, Hordinsky M, Jarrett M, Kang S, Lucky A, Peck G, Phillips T, Rapaport M, Roberts J, Savin R, Sawaya ME, Shalita A, Shavin J, Shaw JC, Stein L, Stewart D, Strauss J, Swinehart J, Swinyer L, Thiboutot D, Washenik K, Weinstein G, Whiting D, Pappas F, Sanchez M, Terranella L, Waldstreicher J. A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris. J Am Acad Dermatol. 2004; 50 443-447
- 14 Bowring N. The development of BRL 7660 as an anti-acne agent. Skinmed. 2005; 4 211-213
- 15 Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol. 1999; 113 1011-1020
- 16 Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988; 106 761-778
- 17 Zouboulis CC, Garbe C, Krasagakis K, Krüger S, Schröder K, Orfanos CE. A fluoremetric rapid microassay to identify anti-proliferative compounds for human melanoma cells in vitro. Melanoma Res. 1991; 1 91-95
- 18 Thiboutot D, Martin P, Volikos L, Gilliland K. Oxidative activity of the type 2 isozyme of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) predominates in human sebaceous glands. J Invest Dermatol. 1998; 111 390-395
- 19 Rosenfield RL, Deplewski D, Kentsis A, Ciletti N. Mechanisms of androgen induction of sebocyte differentiation. Dermatology. 1998; 196 43-46
- 20 Akamatsu H, Zouboulis CC, Orfanos CE. Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands. J Invest Dermatol. 1992; 99 509-511
- 21 Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, Mitra S, Toney J, Bakshi RK, Rasmusson GR, Tolman RL, Harris GS. MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase. J Steroid Biochem Mol Biol. 1996; 58 377-384
- 22 Schwartz JI, Tanaka WK, Wang DZ, Ebel DL, Geissler LA, Dallob A, Hafkin B, Gertz BJ. MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen. J Clin Endocrinol Metab. 1997; 82 1373-1377
- 23 Tian G, Stuart JD, Moss ML, Domanico PL, Bramson HN, Patel IR, Kadwell SH, Overton LK, Kost TA, Mook Jr RA. et al . 17β-(N-tert-butylcarbomoyl)-4-aza-5α-androstane-1-en-3-one is an active site directed slow time-dependent inhibitor of human steroid 5α-reductase 1. Biochemistry J. 1994; 33 2291-2296
- 24 Imperato-Mc Ginley J, Gautier T, Cai L-Q, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab. 1993; 76 524-528
- 25 Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, Nguyen HH, Moore EC, Tanaka WK. The effect of finasteride a 5α-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentration in patients with male pattern baldness. J Clin Endocrinol Metab. 1994; 79 703-706
- 26 Kaufman KD, Olsen EA, Whiting D, Savin R, De Villez R, Bergfeld W, Price VH, Van Neste D, Roberts JL, Hordinsky M, Shapiro J, Binkowitz B, Gormley GJ. Finasteride in the treatment of men with androgenic alopecia. Finasteride male pattern hair loss study group. J Am Acad Dermatol. 1998; 39 578-589
- 27 Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute woman. J Clin Endocrinol Metab. 1995; 80 233-238
- 28 Di Salle E, Guidici D, Briatico G, Ornati G, Panzeri A. Hormonal effects of turosteride, a 5α-reductase inhibitor in the rat. J Steroid Biochem Mol Biol. 1993; 46 549-555
- 29 Iehle C, Delso S, Guirou O, Tate R, Raynaud JP, Martin PM. Human prostatic steroid 5α-reductase isoforms - a comparative study of selective inhibitors. J Steroid Biochem Molec Biol. 1995; 54 273-279
- 30 Mowszowicz I, Wright F, Vincens M, Rigaud C, Nahoud K, Mavier P, Guillemant S, Kuttenn F, Mauvais-Jarvis P. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem. 1984; 20 757-761
- 31 Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J. Antiandrogenic affects of spironolactones: mechanism of action. Endocrinology. 1975; 97 52-58
- 32 Serafini PC, Catalino J, Lobo RA. The effect of spironolactone on genital skin 5α-reductase activity. J Steroid Biochem. 1985; 23 191-194
- 33 Bouton MM, Lecaque D, Secchi J, Tournemine C. Effect of a new topically active antiandrogen (RU 38882) on the rat sebaceous gland: comparison with cyproterone acetate. J Invest Dermatol. 1986; 86 163-167
- 34 Battmann T, Bonfils A, Branche C, Humbert J, Goubet F, Teutsch G, Philibert D. RU 58841, a new specific topical antiandrogen: a candidate of choice for the treatment of acne, androgenetic alopecia and hirsutism. J Steroid Biochem Molec Biol. 1994; 48 55-60
- 35 Fimmel S, Saborowski A, Térouanne B, Sultan C, Zouboulis CC. Inhibition of the androgen receptor by antisense oligonucleotides regulates the biological activity of androgens in SZ95 sebocytes. Horm Metab Res. 2007; , in press
- 36 Zouboulis CC, Eady A, Philpott M, Goldsmith LA, Orfanos C, Cunliffe WJ, Rosenfield R. What is the pathogenesis of acne?. Exp Dermatol. 2005; 14 143-152
1 The work was performed at the Department of Dermatology, University Medical Center Benjamin Franklin, Freie Universitaet Berlin, Berlin, Germany
Correspondence
C. C. Zouboulis
Departments of Dermatology and Immunology
Dessau Medical Center
Dessau
Germany
Telefon: +49/340/501 40 00
Fax: +49/340/501 40 25
eMail: christos.zouboulis@klinikum-dessau.de