On the role of skin in the regulation of local and systemic steroidogenic activities

Abstract

The mammalian skin is a heterogeneous organ/tissue covering our body, showing regional variations and endowed with neuroendocrine activities. The latter is represented by its ability to produce and respond to neurotransmitters, neuropeptides, hormones and neurohormones, of which expression and phenotypic activities can be modified by ultraviolet radiation, chemical and physical factors, as well as by cytokines. The neuroendocrine contribution to the responses of skin to stress is served, in part, by local synthesis of all elements of the hypothalamo-pituitary-adrenal axis. Skin with subcutis can also be classified as a steroidogenic tissue because it expresses the enzyme, CYP11A1, which initiates steroid synthesis by converting cholesterol to pregnenolone, as in other steroidogenic tissues. Pregnenolone, or steroidal precursors from the circulation, are further transformed in the skin to corticosteroids or sex hormones. Furthermore, in the skin CYP11A1 acts on 7-dehydrocholesterol with production of 7-dehydropregnolone, which can be further metabolized to other Δ7steroids, which after exposure to UVB undergo photochemical transformation to vitamin D like compounds with a short side chain. Vitamin D and lumisterol, produced in the skin after exposure to UVB, are also metabolized by CYP11A1 to several hydroxyderivatives. Vitamin D hydroxyderivatives generated by action of CYP11A1 are biologically active and are subject to further hydroxylations by CYP27B1, CYP27A1 and CP24A. Establishment of which intermediates are produced in the epidermis in vivo and whether they circulate on the systemic level represent a future research challenge. In summary, skin is a neuroendocrine organ endowed with steroid/secosteroidogenic activities

Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes

“…Only 1,25(OH) 2 D 3 strongly induced the expression of CYP24A1 which encodes the 24-hydroxylase that inactivates 1,25(OH) 2 D 3 , (Fig. 2C), while 20(OH)D 3 caused modest stimulation, in agreement with previous investigations (reviewed in Slominski et al (2015a,b,c)). All secosteroids tested significantly stimulated the expression of the xenobiotic metabolizing enzyme, CYP3A4, at the mRNA level (Fig.…”

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…Over 12 years we have documented the existence of new pathways of vitamin D3 metabolism started by the action of CYP11A1 and further modified by the actions of CYP27B1, CYP27A1, CYP24A1 and CYP3A4, generating at least 21 hydroxymetabolites with additional ones still to be experimentally defined (Table 1) [43, 50]. At least 13 of them are endogenously produced [72].…”

“…This involved hydroxylations at C22 and C20 followed by oxidative cleavage of the bond between C20 and C22 to produce pregnenolone, a precursor to all steroids [41, 42]. However, the expression of CYP11A1 in peripheral tissues, albeit at low levels, has now been documented [43] and alternative substrates to cholesterol have been identified experimentally, such as 7DHC, vitamins D2 and D3, ergosterol and lumisterol [44–49]. Additionally, the possibility of other sterol/secosteroidal compounds serving as substrates has been predicted theoretically based on molecular modeling [50].…”

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

“…These protective effects are also seen for the novel, CYP11A1-derived hydroxy-derivatives of vitamin D as demonstrated in human epidermal cells [21], and mouse skin in vivo [64]. Since the predominant effect of UVA irradiation, which has no effect on cutaneous vitamin D production, is to generate reactive oxygen species (ROS), active forms of vitamin D may accelerate elimination of cells with neoplastic potential induced by ROS, which would be consistent with their role as protectors of epidermal integrity [65]. Here we have documented the relationship between vitamin D and oxidative stress in human epidermal keratinocytes, and their interplay with the anticancer drug, cisplatin.…”