Enhanced ROS production and redox signaling with combined arsenite and UVA exposure: contribution of NADPH oxidase.
Solar ultraviolet radiation (UVR) is the major etiological factor in skin carcinogenesis. However, in vivo studies demonstrate that mice exposed to arsenic and UVR exhibit significantly more tumors and oxidative DNA damage than animals treated with either agent alone. Interactions between arsenite and UVR in the production of reactive oxygen species (ROS) and stress-associated signaling may provide a basis for the enhanced carcinogenicity. In this study keratinocytes were pretreated with arsenite (3 microM) and then exposed to UVA (10 kJ/m(2)). We report that exposure to UVA after arsenite pretreatment enhanced ROS production, p38 MAP kinase activation, and induction of a redox-sensitive gene product, heme oxygenase-1, compared to either stimulus alone. UVR exposure resulted in rapid and transient NADPH oxidase activation, whereas the response to arsenite was more pronounced and persistent. Inhibition of NADPH oxidase decreased ROS production in arsenite-treated cells but had little impact on UVA-exposed cells. Furthermore, arsenite-induced, but not UVA-induced, p38 activation and HO-1 expression were dependent upon NADPH oxidase activity. These findings indicate differences in the mechanisms of ROS production by arsenite and UVA that may provide an underlying basis for the observed enhancement of redox-related cellular responses upon combined UVA and arsenite exposure.
College of Pharmacy, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131, USA.
Karen L
KL
Cooper
Ke Jian
KJ
Liu
Laurie G
LG
Hudson
D000818:Animals; D018053:Arsenites / Q000009:adverse effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018053:Arsenites; D017382:Reactive Oxygen Species; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C015001:arsenite