Thioredoxin reductase — its role in epidermal redox status

Abstract

The human epidermis with an area of 1.8 m 2 is the outer most layer of the human body. Hence, this organ plays a pivotal role in the defence against reactive oxygen species (ROS) generated by UV or X-ray exposure, heat and other sources. Consequently, a plethora of defence mechanisms exist controlling the redox status in this compartment. The role of thioredoxin reductase (TR), thioredoxin (T) in antioxidant defence has gained widespread recognition. In the past it has been shown that thioredoxin protects against UVB-induced skin injury, as well as against peroxidative damage. Under normal conditions, TR reduces oxidised thioredoxin in the presence of NADPH. Reduced thioredoxin serves as an electron donor for thioredoxin peroxidase (TPx) which consequently reduces H 2O 2 to H 2O. In this context, it has been demonstrated that membrane associated TR correlates with different skin photo types I–VI (Fitzpatrick classification), where darker skin has significantly higher enzyme activity compared to very fair skin, underlining the importance of this system in ROS defence. Moreover, it was only recently demonstrated in vivo with non-invasive Fourier-Transform Raman spectroscopy that UVB generates H 2O 2 in the epidermis in a dose-dependent manner. H 2O 2 can oxidise the selenocysteine residue in the penultimate position of the carboxyl terminus of TR with a K m of 2.5 mM. This oxidation is followed by an upregulation of mRNA expression of the enzyme. Hence, it can be concluded that UVB generated H 2O 2 induces TR. However, permanent H 2O 2 levels induce the tumour suppressor p53 which in turn downregulates cytosolic TR. Therefore TR activities are under fine control by H 2O 2. This conclusion is also supported by the observation that thioredoxin, the substrate for TR, migrates from the cytosol to the nucleus after UVB exposure. A new function for the TR/T/TPx system in epidermal cells has been discovered in the control of the important cofactor (6 R)- l-erythro 5,6,7,8 tetrahydrobiopterin (6BH 4) homeostasis. Full oxidation of 6BH 4 to 6 biopterin via H 2O 2 can lead to a cytotoxic environment for epidermal melanocytes. This cascade of events is observed in the depigmentation disorder vitiligo, where millimolar levels of H 2O 2 can accumulate in the epidermis of affected individuals, consequently leading to cellular vacuolation in this compartment.