Copper/Zinc Superoxide Dismutase in Human Skin: Current Knowledge

Abstract

Superoxide dismutase is widespread in the human body, including skin and its appendages. Here, we focus on human skin copper/zinc superoxide dismutase, the enzyme that protects skin and its appendages against reactive oxygen species. Human skin copper/zinc superoxide dismutase resides in the cytoplasm of keratinocytes, where up to 90% of cellular reactive oxygen species is produced. Factors other than cell type, such as gender, age and diseased state influence its location in skin tissues. We review current knowledge of skin copper/zinc superoxide dismutase including recent studies in an attempt to contribute to solving the question of its remaining unexplained functions. The research described here may be applicable to pathologies associated with oxidative stress. However, recent studies on copper/zinc superoxide dismutase in yeast reveal that its predominant function may be in signaling pathways rather than in scavenging superoxide ions. If confirmed in the skin, novel approaches might be developed to unravel the enzyme's remaining mysteries.

Keywords: Cu/Zn superoxide dismutase; ROS; human skin; immunochemistry; skin tumors.

Figure 1

Scheme of ROS signaling/effects and defense system in the skin. Exogenous and endogenous agents of skin cells generate ROS, whose excessive levels can cause cell damage. ROS modulate MAP signaling pathways leading to activation of the transcription factor AP-1 (activator protein 1) and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells). They also induce: (A) a decrease in procollagen synthesis via blocking TGF-β/SMAD signaling; (B) an increase in the inflammatory processes; (C) an increase in collagen degradation via synthesis of matrix degenerating MMPs. Furthermore, ROS allow nuclear factor Nrf2 to detach from its cytoplasmic inhibitor, keap-1, to translocate to the nucleus and activate transcription of antioxidant genes. Melatonin (8) and α-MSH (9) are also stimulated by ROS to activate Nrf2 dependent-pathways and then the expression of antioxidant genes. The Nrf2 pathway is activated not only in different skin cells such as keratinocytes and melanocytes, but also in fibroblasts (10). Modified by Sardy (11).

Figure 2

Structure of the normal human epidermis (man, aged 25; forearm skin). (A) Section of human skin showing the different layers of the epidermis. OPA trichrome staining (47). 40 x magnification; (B) The enzyme is clearly present in epithelial keratinocytes. Horseradish peroxidase development. Methyl green counterstaining allows a better identification of SOD1-immunoreactive nuclei (arrows). Specimens are subsequently evaluated by histo-densitometry of Cu/Zn SOD immunoreactive areas. 10x magnification. Illustration of BCC (man, aged 71; back, scapular skin). (C) Structure of the epidermis showing a nodular lesion in the dermis. Hematoxylin-Eosin. 10x magnification; (D) Densitometric measurements of Cu/Zn SOD for basal carcinomas were made at the level of the surface epidermis and in the tumor areas invaginated in the dermis. Faint staining of epidermis. Horseradish peroxidase development. Methyl green counterstaining. 10x magnification. Illustration of SCC (woman, aged 65; back, scapular skin). (E) Structure of the SCC-affected skin. Hematoxylin-Eosin. 10x magnification; (F) Densitometric measurements of Cu/Zn SOD in SCC-affected human skin were made at the level of the surface epidermis and in the tumor areas invaginated in the dermis. Epidermal staining is weaker than normal tissue. Horseradish peroxidase development. Methyl green counterstaining. 10x magnification.