Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes

Abstract

Arsenic is a naturally occurring element that is present in food, soil, and water. Inorganic arsenic can accumulate in human skin and is associated with increased risk of skin cancer. Oxidative stress due to arsenic exposure is proposed as one potential mode of carcinogenic action. The purpose of this study is to investigate the specific reactive oxygen and nitrogen species that are responsible for the arsenic-induced oxidative damage to DNA and protein. Our results demonstrated that exposure of human keratinocytes to trivalent arsenite caused the generation of 8-hydroxyl-2'-deoxyguanine (8-OHdG) and 3-nitrotyrosine (3-NT) in a concentration- and time-dependent manner. Pentavalent arsenate had similar effects, but to a significantly less extent. The observed oxidative damage can be suppressed by pre-treating cells with specific antioxidants. Furthermore, we found that pre-treating cells with Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), or with 5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride (FeTMPyP), a decomposition catalyst of peroxynitrite, suppressed the generation of both 8-OHdG and 3-NT, which indicated that peroxynitrite, a product of the reaction of nitric oxide and superoxide, played an important role in arsenic-induced oxidative damage to both DNA and protein. These findings highlight the involvement of peroxynitrite in the molecular mechanism underlying arsenic-induced human skin carcinogenesis.

As(III) inhibits ultraviolet radiation-induced cyclobutane pyrimidine dimer repair via generation of nitric oxide in human keratinocytes

“…2A). This concurs with previous results from our lab demonstrating generation of 3-nitrotyrosine, a product of peroxynitrite and an indirect indicator of NO generation in HaCat cells (27). Blocking iNOS activity with specific inhibitors not only abolished the increase in NO production ( Fig.…”

“…We reported previously that exposure of human keratinocytes to As(III) caused the generation of 3-nitrotyrosine, a biomarker of oxidative protein damage induced by excessive NO and superoxide, in a concentration-and time-dependent manner (27). However, there is little information on As(III)-stimulated NO production at low As(III) concentration, and on the source of NO production.…”

“…Furthermore, the mechanism by which As(III) inhibits CPDs repair is unclear. Because of evidence that As(III) induced the generation of NO in human keratinocytes (27) and in other cells types (28), we set out in the present study to determine whether As(III)-mediated NO production interferes with repair of UVR-induced CPDs formation in human keratinocytes, and to identify the As(III)-stimulated signaling pathway that leads to production of NO. We find that low concentrations of As(III) inhibit UVR-induced CPDs repair and this activity is dependent upon p38 MAPK-mediated signaling via NF-κB leading to induction of iNOS expression.…”

A comparative study on the antioxidant and immunomodulatory properties of curcumin conjugated gold nanospheres and free curcumin

“…These may include free radicals such as superoxide anions radicals (O 2 -), hydroxyl radicals (OH) and non-free radicals such as hydrogen peroxide (H 2 O 2 ) and singlet oxygen (O -) species (Gulcin, 2006). They actually can cause damage to biomolecules including nucleic acids, proteins, and carbohydrates (Ding et al, 2005). If the levels of ROS and RNS are not optimized, they can lead to severe cellular dysfunction (Halliwell and Gutteridge, 1990).…”

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

“…Accumulating evidence suggests that oxidative stress occurs in response to arsenic exposure [5,6] and may be one factor in dermal arsenic carcinogenesis. Indeed, evidence of arsenic-induced oxidative DNA damage has been observed in cells [7][8][9][10][11][12], in rodents [13] and in humans [14].…”