Cytochromes P450 and Skin Cancer: Role of Local Endocrine Pathways

Abstract

Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7-steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.

The role of melanogenesis in regulation of melanoma behavior: Melanogenesis leads to stimulation of HIF-1α expression and HIF-dependent attendant pathways

“…Interestingly, we observed melanogenesis-dependent stimulation of CYP11A1, CYP11B1, 3βHSD , but inhibition of CYP17A1, CYP21A2, HSD11B1, HSD11B2 and 7DHCR (Table 7). Together, these results imply that there is HIF-1 independent regulation of steroidogenesis in pigment cells, similar to the complexity of the pathways operating in the skin [reviewed in [13, 17, 18]]. In the context of downregulation of 7DHCRF, which contains several putative HREs, we speculate that HIF-1 might be involved in the inhibition of cholesterol production by attenuation of reduction of unsaturated B ring and the corresponding accumulation of 7DHC.…”

“…Therefore, there is an urgent need for additional research in order to better define the molecular mechanisms that underline the ability of melanomas to re-wire metabolic and homeostatic responses that are permissive to development of resistance to targeted therapies [11]. Melanoma behavior is driven by several growth factors and cytokines that interact with their corresponding receptors [1, 7, 11], as well as various hormones, neuropeptides and neurotransmitters [12, 13], These include proopiomelanocortin (POMC)-derived peptides ([14, 15] corticotropin releasing hormone (CRH) [16], steroids [17], biogenic amines and melatonin [18, 19]. …”

Secondary Plant Metabolites for Sun Protective Cosmetics: From Pre-Selection to Product Formulation

“…Endogenous intracutaneous melatonin and its metabolites, which are formed in enzymatic and non-enzymatic oxidation reactions, appear to represent the most potent antioxidants against UV irradiation-induced oxidative stress and carcinogenesis due to their hydroxyl radical scavenging properties [41,42]. Melatonin-derived metabolites exerting antioxidant properties (6-hydroxymelatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, and 5-methoxytryptamine) were detected in three types of normal human skin cells, keratinocytes, melanocytes, and dermal fibroblasts [43].…”

Mechanisms of skin aging

“…Intrinsic skin factors such as the local steroidogenic system also have an important role in cutaneous protection against harmful effects of UV-radiation as it is capable of synthesizing androgens, estradiols, gluco-and mineralo-corticoids from precursors, all of which play anti-cancer roles by getting converted into secosteroids under the influence of UV-radiation (55). Additionally, chromophores such as urocanic acid, which is formed from L-histidine in the stratum corneum, is a potent endogenous UV-absorbant (56).…”