Cytochromes P450 and skin cancer

Role of local endocrine pathways

Andrzej T. Slominski, Michal A. Zmijewski, Igor Semak, Blazej Zbytek, Alexander Pisarchik, Wei Li, Jordan Zjawiony, Robert C. Tuckey

Research output: Contribution to journalReview article

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)77-96
Number of pages20
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2014

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Cholesterol Side-Chain Cleavage Enzyme
Skin Neoplasms
Cytochrome P-450 Enzyme System
Skin
Hydroxylation
Secosteroids
Adrenal Cortex Hormones
Skin Physiological Phenomena
Steroids
Cholecalciferol
Sterols
Melatonin
Mixed Function Oxygenases
Vitamin D
Androgens
Neoplasms
Estrogens
Carcinogenesis
Homeostasis
Cholesterol

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Molecular Medicine
  • Pharmacology

Cite this

Slominski, A. T., Zmijewski, M. A., Semak, I., Zbytek, B., Pisarchik, A., Li, W., ... Tuckey, R. C. (2014). Cytochromes P450 and skin cancer: Role of local endocrine pathways. Anti-Cancer Agents in Medicinal Chemistry, 14(1), 77-96. https://doi.org/10.2174/18715206113139990308

Cytochromes P450 and skin cancer : Role of local endocrine pathways. / Slominski, Andrzej T.; Zmijewski, Michal A.; Semak, Igor; Zbytek, Blazej; Pisarchik, Alexander; Li, Wei; Zjawiony, Jordan; Tuckey, Robert C.

In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 14, No. 1, 01.01.2014, p. 77-96.

Research output: Contribution to journalReview article

Slominski, AT, Zmijewski, MA, Semak, I, Zbytek, B, Pisarchik, A, Li, W, Zjawiony, J & Tuckey, RC 2014, 'Cytochromes P450 and skin cancer: Role of local endocrine pathways', Anti-Cancer Agents in Medicinal Chemistry, vol. 14, no. 1, pp. 77-96. https://doi.org/10.2174/18715206113139990308
Slominski, Andrzej T. ; Zmijewski, Michal A. ; Semak, Igor ; Zbytek, Blazej ; Pisarchik, Alexander ; Li, Wei ; Zjawiony, Jordan ; Tuckey, Robert C. / Cytochromes P450 and skin cancer : Role of local endocrine pathways. In: Anti-Cancer Agents in Medicinal Chemistry. 2014 ; Vol. 14, No. 1. pp. 77-96.
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AU - Zbytek, Blazej

AU - Pisarchik, Alexander

AU - Li, Wei

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