8-hydroxyguanosine and Vitiligo

Vitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76(MDM2). Short-patch base-excision repair via hOgg1, APE1, and polymerasebeta DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO(-)) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-oxidized p53 (10(-3) M) enhances DNA binding capacity and prevents ONOO(-)-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76(MDM2) as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.

Topics: Adult; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Caspase 3; Cell Cycle Proteins; Cytochromes c; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Electrophoretic Mobility Shift Assay; Epidermis; Guanosine; Humans; Hydrogen Peroxide; Middle Aged; Oxidation-Reduction; Oxidative Stress; p300-CBP Transcription Factors; Peroxynitrous Acid; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Vitiligo