Biological Effects of CYP11A1-Derived Vitamin D and Lumisterol Metabolites in the Skin

Abstract

Novel pathways of vitamin D3, lumisterol 3 (L3), and tachysterol 3 (T3) activation have been discovered, initiated by CYP11A1 and/or CYP27A1 in the case of L3 and T3. The resulting hydroxymetabolites enhance protection of skin against DNA damage and oxidative stress; stimulate keratinocyte differentiation; exert anti-inflammatory, antifibrogenic, and anticancer activities; and inhibit cell proliferation in a structure-dependent manner. They act on nuclear receptors, including vitamin D receptor, aryl hydrocarbon receptor, LXRα/β, RAR-related orphan receptor α/γ, and peroxisome proliferator-activated receptor-γ, with selectivity defined by their core structure and distribution of hydroxyl groups. They can activate NRF2 and p53 and inhibit NF-κB, IL-17, Shh, and Wnt/β-catenin signaling. Thus, they protect skin integrity and physiology.

Keywords: Lumisterol; Nuclear receptors; Skin; Tachysterol; Vitamin D receptors.

Figure 1.

Novel pathways of vitamin D3, lumisterol3 and tachysterol3 activation. Vitamin D3 (D3), lumisterol3 (L3), tachysterol3 (T3) and 7DHC are substrates for CYP11A1 that by itself or in cooperation with other CYPs (including CYP27A1, CYP2R1, CYP3A4, CYP24A1 and CYP27B1) produces the derivatives as shown. In the case of lumisterol3 and 7HDC, the side chain can be cleaved by CYP11A1 to produce 7-dehydropregnenolone (7DHP) or pregna-lumisterol (pL) that can be further metabolized by other steroidogenic enzymes. Production of tachysterol derivatives by CYP11A1 or CYP27A1 is also presented. Photoproduction of pregna-calciferol (pD), pL and pregna-tachysterol (pT), as well as of D3, L3 and T3 hydroxyderivatives after exposure of Δ7-precursors to UVB, are also shown. Structures show carbon numbers indicating potential sites of hydroxylation. ΔT represents the temperature-driven transformation of pre-D3 to the D3 configuration.

Figure 2.

Biological activity and mechanism of action in the skin of locally produced and enzymatically activated vitamin D3, lumisterol3 and tachysterol3 metabolites. RORs: retinoid-related orphan receptor α and γ; G-VDR: genomic binding site of the vitamin D receptor, A-VDR: non-genomic binding site of the VDR, AhR: aryl hydrocarbon receptor, LXRs: liver X receptor α and β; PPARγ: peroxisome proliferator-activated receptor gamma, SHH: sonic hedgehog, NRF-2: nuclear factor erythroid 2-related factor 2, NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells, 7DHC: 7-dehydrocholesterol, D3: vitamin D3, L3: lumisterol3, T3: tachysterol3. Arrows pointing up or down represent stimulation or inhibition. There are also nuclear receptor independent mechanisms of action, which are discussed in the main text.