Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewInflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis
Introduction
Ultraviolet (UV) radiation that reaches the surface of the Earth from the sun is divided into two wavebands, UVB (290–320 nm) and UVA (320–400 nm), with visible light being at longer wavelengths. UV can cause direct biological damage, or indirect damage via the production of reactive oxygen species (ROS). ROS cause oxidative damage to DNA, proteins and lipids. Whereas UVB and UVA both cause oxidative damage, UVA is generally regarded to cause a large amount of its deleterious effects via this mechanism, whereas UVB is generally regarded to mainly cause direct damage. UVA induction of ROS is important for at least some of the biological effects of this waveband [1].
UV radiation increases the activity of xanthine oxidase in human keratinocytes, increasing production of superoxide [2]. Additionally there are a variety of chromophores, such as porphyrins and heme in human skin, which could produce ROS in response to UVA radiation; however, these remain poorly defined [3], [4], [5]. UVA produces a variety of ROS in the skin, including superoxide and hydrogen peroxide (Fig. 1). All of these are likely to contribute to the damaging biological effects of UVA on DNA, lipids and proteins [3]. The epidermis contains antioxidant defenses including the enzymes, superoxide dismutase, glutathione peroxidase and catalase, which remove ROS from the skin [6]. Free radical scavengers, such as Vitamins C and E, carotenoids and glutathione are also present in the skin to reduce the damaging effects of ROS. Increased production of ROS following exposure to UV can deplete these antioxidant defences, leaving the skin vulnerable to attack from ROS [7].
Nitric oxide (NO) is produced by a family of inducible, neural and endothelial NO synthase (iNOS, nNOS and eNOS, respectively) from l-arginine. Both UVA and UVB activate NOS in the skin, increasing levels of NO [8], [9]. NO, produced by UV upregulated nitric oxide synthase can combine with UV-induced superoxide to form peroxynitrite that exists in equilibrium with peroxynitrous acid. These reactive nitrogen species are very toxic, and can cause DNA damage, nitrosylation of tyrosine residues in proteins, and initiate lipid peroxidation, all of which interfere with cellular function.
Poly(ADP-ribose) polymerase (PARP) is activated in response to DNA damage caused by peroxynitrite. It breaks down NAD+ into nicotinamide and ADP-ribose, leading to a shortage of this molecule in skin cells, which in turn reduces ATP formation. The ensuing low energy level disrupts cell function, and in extreme cases cell death ensues [10]. UV radiation has been shown to reduce NAD+ levels in the skin [11]. Thus, another consequence of UV-induced NO and superoxide production is peroxynitrite leading to cellular energy loss.
Inflammatory cells, such as macrophages and neutrophils, also produce large amounts of ROS and NO resulting in peroxynitrite formation, DNA damage NAD+ depletion and energy loss from cells [12], [13], [14]. This is likely to be an important mechanism of damage to tissues and cells being targeted by the inflammatory cells. These events are similar in many ways to UVA-induced oxidative damage. As sunlight causes inflammation, oxidative damage could occur either as a direct response to the UVA or indirectly from inflammatory cells activated in response to the sunlight.
UV radiation has many biological effects on the skin that contribute to photocarcinogenesis. Low-level exposure increases synthesis of Vitamin D, which protects from genetic damage and carcinogenesis [15]. High-level exposure causes formation of sunburn cells, which are cells dying of apoptosis. This protects from photocarcinogenesis, as dead cells do not form cancers. At doses in between these UV suppresses immunity and leads to gene mutation. UV also promotes inflammation. These three biological events cause skin cancer. Thus, this review on UV-induced oxidative stress in inflammation, gene mutation and photoimmunosuppression will concentrate on the connection between these events and photocarcinogenesis. An emphasis is given to evidence from whole animal and human studies.
Section snippets
The connection between UV-induced oxidative stress, inflammation and carcinogenesis
UV augments blood flow and infiltration by blood leukocytes, such as macrophages and neutrophils into the skin, observed clinically as inflammation. Increased production of NO and prostaglandins contribute to these events [16], [17]. UV radiation-induced lipid peroxidation increases production of prostaglandins (PG), including PGE2, which in turn cause inflammation in the skin [18]. PGE2 is produced from arachidonic acid by the inducible form of cyclooxygenase (COX), COX-2. This is thought to
UV-induced oxidative damage and gene mutation
There is little direct evidence for oxidative damage to DNA making a substantial contribution to photocarcinogenesis. The formation of micronuclei is an indication of chromosomal rearrangement or genetic instability. UVA-induced micronucleus formation in cultured HaCa T cells was reduced by treatment with catalase suggesting a role for hydrogen peroxide in this form of UVA-induced genetic damage [47].
UVB absorbed by two adjacent cytosine (C) residues in DNA causes the formation of cyclobutane
UV-induced oxidative stress and photoimmunosuppression
Both UVB and UVA suppress the immune system of humans and mice. UVB-induces immunosuppression by events downstream from DNA absorption forming pyrimidine dimers [58] or trans urocanic acid absorption of UVB, so that it isomerises to the immunosuppressive cis form [59], [60]. UVA is also immunosuppressive in both humans [61], [62] and mice [63], [64]. A number of studies have shown that to prevent immunosuppression in response to solar-simulated UV radiation (containing a mixture of UVB and UVA
Antioxidants reduce skin carcinogenesis
Finally, antioxidants have been shown to reduce photocarcinogenesis, and whereas it is not always clear whether they mediated this effect by preventing inflammation, gene mutation or immunosuppression, they show that reactive oxygen or nitrogen is important for photocarcinogenesis. The antioxidant Vitamin E delays or reduces UV radiation-induced skin carcinogenesis in mice, through a reduction in DNA damage, immunosuppression or both [82], [92], [93]. Addition of inhibitors of NO or ROS
Conclusions
Available evidence indicates that UV-induced oxidative stress is important in skin cancer development. Whereas sufficient evidence exists in animal models and humans to support this, many details are not yet known and further research is required in this area. UV radiation in sunlight, particularly the UVA waveband, at physiological doses to which humans are readily exposed is able to produce a range of oxidative stress responses in the skin. These include the production of a variety of
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2022, Journal of EthnopharmacologyCitation Excerpt :Skin-specific molecules or chromophores absorb UV radiation energy, causing direct photochemical damage or indirect oxidative damage to DNA, proteins, and biomembranes. These photobiological skin reactions are the root cause of photoaging and photocarcinogenesis (Halliday, 2005). During normal physiological and biochemical reactions, cells generate free radicals in various ways, while copious amounts of free radicals can appear in the process of cell damage.