The significance of CYP11A1 expression in skin physiology and pathology

Abstract

CYP11A1, a member of the cytochrome P450 family, plays several key roles in the human body. It catalyzes the first and rate-limiting step in steroidogenesis, converting cholesterol to pregnenolone. Aside from the classical steroidogenic tissues such as the adrenals, gonads and placenta, CYP11A1 has also been found in the brain, gastrointestinal tract, immune systems, and finally the skin. CYP11A1 activity in the skin is regulated predominately by StAR protein and hence cholesterol levels in the mitochondria. However, UVB, UVC, CRH, ACTH, cAMP, and cytokines IL-1, IL-6 and TNFα can also regulate its expression and activity. Indeed, CYP11A1 plays several critical roles in the skin through its initiation of local steroidogenesis and specific metabolism of vitamin D, lumisterol, and 7-dehydrocholesterol. Products of these pathways regulate the protective barrier and skin immune functions in a context-dependent fashion through interactions with a number of receptors. Disturbances in CYP11A1 activity can lead to skin pathology.

Keywords: CYP11A1; Corticosteroid biosynthesis; Hypothalamo-pituitaryadrenal axis; Lumisterol; Neuroendocrine functions of the skin; Secosteroids; Skin; Skin barrier function; Skin immune activity; Steroids.

Figure 1.

CYP11A1 activities in the skin. A. CYP11A1 receives electrons form its redox partners to cleave the side chain of cholesterol producing pregnenolone which is converted to other steroids by cell/tissue specific pathways. B. CYP11A1 can act on endogenous sterols and secosteroids in the skin. The major products from cholesterol and 7DHC have their side chain removed whereas little cleavage of the side chain occurs for lumisterol and no cleavage occurs for vitamin D3. Major products from each substrate are shown in bold font. The stereochemistry of products is shown, where known. 7DHC, 7-dehydrocholesterol; lumisterol, lumisterol3. More details on these reactions can be found in (Slominski et al., 2015a; 2020a; Tuckey et al., 2011; Tuckey et al., 2019).

Figure 2.

Immunofluorescent staining of CYP11A1 (P450scc) in skin with and without UV treatment. A shows the human skin and the levels of CYP11A1 and its regulators CRH (corticotropin releasing hormone), PC1 (proconvertase-1), ACTH (adrenocorticotropic), B-END (β-endorphin), and GR (glucocorticoid receptor) after treatment with UVA, UVB, and UVC. Image taken from (Skobowiat et al., 2011) with permission from the publisher. B shows the CYP11A1 levels in the skin of C57BL6 mice and DBA/2J mice before and after treatment with UVB. Image taken from (Skobowiat et al., 2013a) with permission from the publisher.

Figure 3.

Production of cortisol in human skin cells. A. Corticotropin-releasing hormone (CRH) were shown to stimulate proopiomelanocortin (POMC) in melanocytes in a time dependent manner. The top graph shows CRH stimulating mRNA production of POMC. The white bar shows negative control while the black bar shows treatment with CRH. The bottom graph shows CRH stimulating ACTH production in a concentration dependent manner after 24 hours of treatment. B. Melanocytes were shown to produce cortisol. The top graph shows liquid chromatography-mass spectrometry (LC/MS) of cortisol control vs melanocyte extract. Notice that both of them have a peak of [M+H]+ at mass to charge ratio of 363 with retention time at 11 minutes. The last two graphs come from mass spectrometry fragmentation analysis and shows similarities between melanocytes extract (middle graph) and cortisol standard (bottom graph). C. CRH was shown to promote cortisol production in melanocytes in POMC and CRH-R1 dependent manner. D. Fibroblasts were shown to produce cortisol. The top graph shows liquid chromatography-mass spectrometry (LC/MS) of cortisol standard vs fibroblasts extract. Notice that both of them have a peak of [M+H]+ at mass to charge ratio of 363 with retention time at 11 minutes. The last two graphs come from mass spectrometry fragmentation analysis and shows similarities between fibroblast containing media (middle graph) and cortisol standard (bottom graph). Panels A, B, and C were taken with permission from the following article (Slominski at al. 2005c) and panel D was taken with permission from the publisher (Slominski et al., 2006b).

Figure 4.

Summary of the two-edged role that CYP11A1-derived compounds play in the human skin.