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November 20, 1991, Vol 266, No. 19 >
ARTICLE | November 20, 1991

Induction of Skin Tanning by Subcutaneous Administration of a Potent Synthetic Melanotropin FREE

Norman Levine, MD; Scott N. Sheftel, MD; Ted Eytan; Robert T. Dorr, PhD; Mac E. Hadley, PhD; Jonathan C. Weinrach; Gregory A. Ertl, MD; Katalin Toth, PhD; Daniel L. McGee, PhD; Victor Hruby, PhD
[+] Author Affiliations

Reprint requests to Section of Dermatology, University of Arizona Health Sciences Center, 1501 N Campbell Ave, Tucson, AZ 85724 (Dr Levine).


JAMA. 1991;266(19):2730-2736. doi:10.1001/jama.1991.03470190078033
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References

Objective.  —To determine the efficacy of short-term administration of a synthetic analogue of α-melanotropin, [Nle4D-Phe7] (NDP)—α-melanocyte-stimulating hormone (MSH), in darkening (tanning) human skin.

Design.  —Randomized, placebo-controlled, double-blind clinical trial.

Setting.  —Clinical research unit of a university medical center.

Subjects.  —Twenty-eight healthy white men with a history of either poor tanning (skin type I or II) or good tanning (skin type III or IV) recruited from advertisements and paid to participate in the study.

Methods.  —Each subject received 10 subcutaneous injections of either a purified NDP preparation or saline over 12 days. They were followed up for 7 weeks after therapy was completed. All subjects used a high-potency sunscreen during the the trial.

Main Outcome Measure.  —Skin darkening was quantified by serial chromaticity measurements prior to, during, and after therapy.

Results.  —A significant parabolic curve of skin darkening activity was noted in subjects with skin type I or II (P,.001) and with skin type III or IV (P<<.001) who were given NDP. No darkening occurred in the subjects who were given a placebo. Peak changes were seen 1 to 3 weeks after therapy was completed.

Conclusion.  —Human skin darkens as a response to a synthetic melanotropin given by subcutaneous injection. Skin tanning appears possible without potentially harmful exposure to ultraviolet radiation.(JAMA. 1991;266:2730-2736)

REFERENCES

1 +
Hadley ME. Endocrinology . 2nd ed. Englewood Cliffs, NJ: Prentice-Hall Inc; 1988;:159.
2 +
Hadley ME, Dawson BV.  Biomedical applications of synthetic melanotropins. Pigment Cell Res . 1988;;1( (suppl 1) ):69-78.
3 +
O'Donohue TL, Dorsa DM.  The opiomelanotropinergic neural and endocrine systems. Peptides . 1982;;3:353-395.
4 +
Gordon PR, Gilchrest BA.  Human melanogenesis is stimulated by diacylglycerol. J Invest Dermatol . 1989;;93:700-702.
5 +
Pawelek JM.  Is human melanogenesis stimulated by cyclic AMP? J Invest Dermatol . 1990;;94:499-500. Letter to the editor.
6 +
Gilchrest BA, Gordon PR.  Is human melanogenesis stimulated by cyclic AMP? J Invest Dermatol . 1990;;94:500. Reply to letter to the editor.
7 +
Mulligan TM, Sowers JR.  Hyperpigmentation, vitiligo, and Addison's disease. Cutis . 1982;;26:317-322.
8 +
Sawyer TK, Hruby VJ, Hadley ME, Engel MH.  α-Melanocyte stimulating hormone: chemical nature and mechanism of action. Am Zool . 1983;;23:529-540.
9 +
Lerner AB, McGuire JS.  Effects of alpha- and beta-melanocyte stimulating hormones on the skin color of man. Nature . 1961;;189:176-179.
10 +
Lerner AB, McGuire JS.  Melanocyte-stimulating hormone and adrenocorticotrophic hormone: their relation to pigmentation. N Engl J Med . 1964;;270:539-546.
11 +
Sawyer TK, Sanfillippo PJ, Hruby VJ, et al.  [Nle4D-Phe7]—α-melanocyte stimulating hormone: a highly potent α-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A . 1980;;77:5754-5758.
12 +
Hruby VJ, Wilkes BC, Cody WL, Sawyer TK, Hadley ME.  Melanotropins: structural, conformational, and biological considerations in the development of superpotent and super prolonged analogs.  In: Hearn MTW, ed. Peptide Protein Review . New York, NY: Marcel Dekker Inc; 1984;;3:1-64.
13 +
Sawyer TK, Hruby VJ, Wilkes BC, Draelos MT, Hadley ME, Bergsneider M.  Comparative biological activities of highly potent active-site analogues of α-melanotropin. J Med Chem . 1982;;25:1022-1027.
14 +
Levine N, Lemus-Wilson SH, Wood SH, Abdel-Malek ZA, Hruby VJ, Hadley ME.  Follicular melanogenesis of the mouse: stimulation by injected and topical melanotropins. J Invest Dermatol . 1987;;89:269-273.
15 +
Dorr RT, Dawson BV, Hadley ME, Levine N, Hruby VJ.  Toxicological studies of a superpotent αmelanotropin, [Nle4D-Phe7]—α-MSH. Invest New Drugs . 1988;;6:251-258.
16 +
Sullivan JD Jr, Valois FW, Watson SW.  Endotoxins: the Limulus amebocyte lysate system.  In: Bernheimer AW, ed. Mechanisms of Bacterial Toxicology . New York, NY: John Wiley & Sons Inc; 1976;:217-220.
17 +
Pathak MA, Fitzpatrick TB, Greiter F, Kraus EW.  Preventive treatment of sunburn, dermatoheliosis, and skin cancer with sun-protective agents.  In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine . New York, NY: McGraw-Hill International Book Co; 1987;:1507-1522.
18 +
Porges SB, Kaidbey KH, Grove GL.  Quantification of visible light-induced melanogenesis in human skin. Photodermatol . 1988;;5:197-200.
19 +
Westerhof W, van Hasselt BAAM, Kammeijer A.  Quantification of UV-induced erythema with a portable computer controlled chromometer. Photodermatol . 1986;;3:310-314.
20 +
Seitz JC, Whitmore CG.  Measurements of erythematous and tanning responses in human skin using a tri-stimulus colorimeter. Dermatologica . 1988;;177:70-75.
21 +
Ware JH.  Linear models for the analysis of longitudinal studies. Am Statistician . 1985;;39:93-102.
22 +
Liang K-Y.  Longitudinal data analysis using generalized linear models. Biostatistics . 1986;;73:13-22.
23 +
Laird WM, Ware JM.  Random-effects models for longitudinal data. Biometrics . 1982;;38:963-974.
24 +
Szabo G.  The number of melanocytes in human epidermis. BMJ . 1954;;1:1016-1017.
25 +
Frienkel RK, Frienkel N.  Cutaneous manifestations of endocrine disorders.  In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine . New York, NY: McGraw-Hill International Book Co; 1987;:2063-2081.
26 +
Bolognia J, Murray M, Pawelek J.  UVB-induced melanogenesis may be mediated through the MSH-receptor system. J Invest Dermatol . 1989;;92:651-656.
27 +
Wilkes BC, Sawyer TK, Hruby VJ, Hadley ME.  Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro. Int J Pept Protein Res . 1983;;22:313-324.
28 +
Abdel-Malek ZA, Kreutzfeld KL, Marwan MM, Hadley ME, Hruby VJ, Wilkes BC.  Prolonged stimulation of S91 melanoma tyrosinase by [Nle4,D-Phe7]-substituted alpha-melanotropins. Cancer Res . 1985;;45:4735-4740.
29 +
Castrucci AML, Hadley ME, Sawyer TK, Hruby VJ.  Enzymological studies of melanotropins. Comp Biochem Physiol . 1984;;78B:519-524.
30 +
Abdel-Malek ZA, Hadley ME, Bregman MD, Meyskens JF Jr, Hruby VJ.  Actions of melanotropins on mouse melanoma cell culture in vitro. J Natl Cane Inst . 1986;;76:857-863.
31 +
Pawelek JM.  Factor regulating growth and pigmentation of melanoma cells. J Invest Dermatol . 1976;;66:201-209.
32 +
Fuller BB, Viskochil DH.  The role of RNA and protein synthesis in mediating the action of MSH on mouse melanoma cells. Life Sci . 1979;;24:2405-2416.
33 +
McGuire JS, Lerner AB.  Effects of tricosopeptide 'ACTH' and alpha-melanocyte stimulating hormone on the skin color of man. Ann N Y Acad Sci . 1963;;100:622-630.
34 +
King RA, Summers CG.  Albinism. Dermatol Clin . 1988;;6:217-228.
35 +
Dawson BV, Hadley ME, Levine N, et al.  In vitro transdermal delivery of a melanotropic peptide through human skin. J Invest Dermatol . 1990;;94:432-435.

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1 +
Hadley ME. Endocrinology . 2nd ed. Englewood Cliffs, NJ: Prentice-Hall Inc; 1988;:159.
2 +
Hadley ME, Dawson BV.  Biomedical applications of synthetic melanotropins. Pigment Cell Res . 1988;;1( (suppl 1) ):69-78.
3 +
O'Donohue TL, Dorsa DM.  The opiomelanotropinergic neural and endocrine systems. Peptides . 1982;;3:353-395.
4 +
Gordon PR, Gilchrest BA.  Human melanogenesis is stimulated by diacylglycerol. J Invest Dermatol . 1989;;93:700-702.
5 +
Pawelek JM.  Is human melanogenesis stimulated by cyclic AMP? J Invest Dermatol . 1990;;94:499-500. Letter to the editor.
6 +
Gilchrest BA, Gordon PR.  Is human melanogenesis stimulated by cyclic AMP? J Invest Dermatol . 1990;;94:500. Reply to letter to the editor.
7 +
Mulligan TM, Sowers JR.  Hyperpigmentation, vitiligo, and Addison's disease. Cutis . 1982;;26:317-322.
8 +
Sawyer TK, Hruby VJ, Hadley ME, Engel MH.  α-Melanocyte stimulating hormone: chemical nature and mechanism of action. Am Zool . 1983;;23:529-540.
9 +
Lerner AB, McGuire JS.  Effects of alpha- and beta-melanocyte stimulating hormones on the skin color of man. Nature . 1961;;189:176-179.
10 +
Lerner AB, McGuire JS.  Melanocyte-stimulating hormone and adrenocorticotrophic hormone: their relation to pigmentation. N Engl J Med . 1964;;270:539-546.
11 +
Sawyer TK, Sanfillippo PJ, Hruby VJ, et al.  [Nle4D-Phe7]—α-melanocyte stimulating hormone: a highly potent α-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A . 1980;;77:5754-5758.
12 +
Hruby VJ, Wilkes BC, Cody WL, Sawyer TK, Hadley ME.  Melanotropins: structural, conformational, and biological considerations in the development of superpotent and super prolonged analogs.  In: Hearn MTW, ed. Peptide Protein Review . New York, NY: Marcel Dekker Inc; 1984;;3:1-64.
13 +
Sawyer TK, Hruby VJ, Wilkes BC, Draelos MT, Hadley ME, Bergsneider M.  Comparative biological activities of highly potent active-site analogues of α-melanotropin. J Med Chem . 1982;;25:1022-1027.
14 +
Levine N, Lemus-Wilson SH, Wood SH, Abdel-Malek ZA, Hruby VJ, Hadley ME.  Follicular melanogenesis of the mouse: stimulation by injected and topical melanotropins. J Invest Dermatol . 1987;;89:269-273.
15 +
Dorr RT, Dawson BV, Hadley ME, Levine N, Hruby VJ.  Toxicological studies of a superpotent αmelanotropin, [Nle4D-Phe7]—α-MSH. Invest New Drugs . 1988;;6:251-258.
16 +
Sullivan JD Jr, Valois FW, Watson SW.  Endotoxins: the Limulus amebocyte lysate system.  In: Bernheimer AW, ed. Mechanisms of Bacterial Toxicology . New York, NY: John Wiley & Sons Inc; 1976;:217-220.
17 +
Pathak MA, Fitzpatrick TB, Greiter F, Kraus EW.  Preventive treatment of sunburn, dermatoheliosis, and skin cancer with sun-protective agents.  In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine . New York, NY: McGraw-Hill International Book Co; 1987;:1507-1522.
18 +
Porges SB, Kaidbey KH, Grove GL.  Quantification of visible light-induced melanogenesis in human skin. Photodermatol . 1988;;5:197-200.
19 +
Westerhof W, van Hasselt BAAM, Kammeijer A.  Quantification of UV-induced erythema with a portable computer controlled chromometer. Photodermatol . 1986;;3:310-314.
20 +
Seitz JC, Whitmore CG.  Measurements of erythematous and tanning responses in human skin using a tri-stimulus colorimeter. Dermatologica . 1988;;177:70-75.
21 +
Ware JH.  Linear models for the analysis of longitudinal studies. Am Statistician . 1985;;39:93-102.
22 +
Liang K-Y.  Longitudinal data analysis using generalized linear models. Biostatistics . 1986;;73:13-22.
23 +
Laird WM, Ware JM.  Random-effects models for longitudinal data. Biometrics . 1982;;38:963-974.
24 +
Szabo G.  The number of melanocytes in human epidermis. BMJ . 1954;;1:1016-1017.
25 +
Frienkel RK, Frienkel N.  Cutaneous manifestations of endocrine disorders.  In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine . New York, NY: McGraw-Hill International Book Co; 1987;:2063-2081.
26 +
Bolognia J, Murray M, Pawelek J.  UVB-induced melanogenesis may be mediated through the MSH-receptor system. J Invest Dermatol . 1989;;92:651-656.
27 +
Wilkes BC, Sawyer TK, Hruby VJ, Hadley ME.  Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro. Int J Pept Protein Res . 1983;;22:313-324.
28 +
Abdel-Malek ZA, Kreutzfeld KL, Marwan MM, Hadley ME, Hruby VJ, Wilkes BC.  Prolonged stimulation of S91 melanoma tyrosinase by [Nle4,D-Phe7]-substituted alpha-melanotropins. Cancer Res . 1985;;45:4735-4740.
29 +
Castrucci AML, Hadley ME, Sawyer TK, Hruby VJ.  Enzymological studies of melanotropins. Comp Biochem Physiol . 1984;;78B:519-524.
30 +
Abdel-Malek ZA, Hadley ME, Bregman MD, Meyskens JF Jr, Hruby VJ.  Actions of melanotropins on mouse melanoma cell culture in vitro. J Natl Cane Inst . 1986;;76:857-863.
31 +
Pawelek JM.  Factor regulating growth and pigmentation of melanoma cells. J Invest Dermatol . 1976;;66:201-209.
32 +
Fuller BB, Viskochil DH.  The role of RNA and protein synthesis in mediating the action of MSH on mouse melanoma cells. Life Sci . 1979;;24:2405-2416.
33 +
McGuire JS, Lerner AB.  Effects of tricosopeptide 'ACTH' and alpha-melanocyte stimulating hormone on the skin color of man. Ann N Y Acad Sci . 1963;;100:622-630.
34 +
King RA, Summers CG.  Albinism. Dermatol Clin . 1988;;6:217-228.
35 +
Dawson BV, Hadley ME, Levine N, et al.  In vitro transdermal delivery of a melanotropic peptide through human skin. J Invest Dermatol . 1990;;94:432-435.

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