Cytochrome P450scc system can efficiently transform 7-dehydrocholesterol (7-DHC) to 7- dehydropregnenolone (7-DHP) and hydroxylate vitamin D2 and D3, and ergosterol. Thus, we uncovered novel steroido/secosteroidogenic pathways generating new biologically active products. The cutaneous pathway would elicit mostly intra-, auto- or paracrine modes of action. In SLOS, UVB light-induced conversions (exclusive for the skin) would proceed with substrates derived from the systemic circulation (5, 7-steroidal dienes) to generate vitDL compounds. These novel pathways could generate a number of molecules with structures determined by the local type and activity of steroidogenic system, as well as the access to UVB photons. To test this hypothesis the following specific aims have been designed. 1. Testing the biological activity of P450scc derived 20-hydroxyvitamin D3 and 20,22 dihydroxyvitamin D3, 17a,24- dihydroxyergosterol, its photolytic derivative, and of 20-hydroxyvitamin D2 and 17a, 20-dihydroxyvitamin D2. The above effects will be compared to the parent compounds, i.e. vitamins D3 and 2, and ergosterol.;2. Testing the biological activity of 7-DHP, its hydroxyderivatives and the secosteroidal products of their photolytical (UVB-induced) transformation;3. Characterization of the enzymatic conversion of 7-DHP into hydroxy-derivatives, particularly at positions 17, 20, 21 and 11. The studies will include synthesis of the standards to fully characterize the chemical structures and properties of the reaction products. 4. Testing the predicted action of UVB in inducing B-ring intramolecular rearrangements of 7-DHP and its hydroxy- derivatives or 17a,24-dihydroxyergostero resulting in the anticipated vitDL - derivatives. Tests of the structural stability of the resulting molecules will also be performed;5. Defining a role for the P450scc in the in vivo metabolism of 5, 7- dienesterols, vitamin D and ergosterol: a) characterization of 7-DHC transformation by P450scc in vivo in cultured skin cells in comparison to an adrenal cell line. Secosteroids production after exposure of the cells to ultraviolet radiation will also be investigated.;b) characterization of vitamin D and ergosterol transformation by P450scc in cultured skin cells. 6. Defining the effect of 7-DHP, its hydroxy and seco-derivatives and of vitamin D (modified or unmodified) on P450scc mediated pregnenolone production from cholesterol.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052190-05
Application #
7903172
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (06))
Program Officer
Baker, Carl
Project Start
2006-08-15
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$376,757
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Jetten, Anton M; Takeda, Yukimasa; Slominski, Andrzej et al. (2018) Retinoic acid-related Orphan Receptor ? (ROR?): connecting sterol metabolism to regulation of the immune system and autoimmune disease. Curr Opin Toxicol 8:66-80
Slominski, Andrzej T; Bro?yna, Anna A; Skobowiat, Cezary et al. (2018) On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol 177:159-170
Tarasen, Ashley; Carlson, J Andrew; Leonard, M Kathryn et al. (2017) Pigmented Epithelioid Melanocytoma (PEM)/Animal Type Melanoma (ATM): Quest for an Origin. Report of One Unusual Case Indicating Follicular Origin and Another Arising in an Intradermal Nevus. Int J Mol Sci 18:
Skobowiat, Cezary; Postlethwaite, Arnold E; Slominski, Andrzej T (2017) Skin Exposure to Ultraviolet B Rapidly Activates Systemic Neuroendocrine and Immunosuppressive Responses. Photochem Photobiol 93:1008-1015
Slominski, Andrzej T; Kim, Tae-Kang; Hobrath, Judith V et al. (2017) Endogenously produced nonclassical vitamin D hydroxy-metabolites act as ""biased"" agonists on VDR and inverse agonists on ROR? and ROR?. J Steroid Biochem Mol Biol 173:42-56
Slominski, Andrzej T; Zmijewski, Michal A (2017) Glucocorticoids Inhibit Wound Healing: Novel Mechanism of Action. J Invest Dermatol 137:1012-1014
Skobowiat, Cezary; Oak, Allen S W; Kim, Tae-Kang et al. (2017) Noncalcemic 20-hydroxyvitamin D3 inhibits human melanoma growth in in vitro and in vivo models. Oncotarget 8:9823-9834
Slominski, Andrzej T; Bro?yna, Anna A; Zmijewski, Michal A et al. (2017) Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. Lab Invest 97:706-724
Lin, Zongtao; Marepally, Srinivasa R; Ma, Dejian et al. (2016) Synthesis and Biological Evaluation of Vitamin D3 Metabolite 20S,23S-Dihydroxyvitamin D3 and Its 23R Epimer. J Med Chem 59:5102-8
Skobowiat, Cezary; Slominski, Andrzej T (2016) Ultraviolet B stimulates proopiomelanocortin signalling in the arcuate nucleus of the hypothalamus in mice. Exp Dermatol 25:120-3

Showing the most recent 10 out of 126 publications