ROS: a step closer to elucidating their role in the etiology of light-induced skin disorders.

Abstract

Free radicals are chemical species characterized by an odd number of orbital electrons, or by pairs of electrons of similar directional spin isolated singly in separate orbitals. Consequently, most of these agents are highly reactive and usually exhibit an extremely short half-life, although due to steric and resonance effects, some exceptions occur. For example, the diradical, molecular oxygen, exists in the triplet state (O2) and is an essential element of normal metabolism of aerobic organisms. Even under normal circumstances, however, the controlled reduction of oxygen occurs and leads to the formation of the major reactive oxygen species (ROS), i.e., superoxide anion, hydrogen peroxide, and hydroxyl radical. Singlet oxygen, although technically not a free radical, is highly reactive and may produce biological effects similar to those of other ROS. In addition to ROS, organisms may be subjected to a wide array of other free radicals, including those of both exogenous and endogenous origin. This is particularly true of the skin. Almost every major class of cellular chemical constituent (e.g., lipids, nucleic acids, and proteins) is subject to radical attack, providing a rationale for the involvement of free radical reactions in the pathophysiology of a wide spectrum of disorders. Although the idea that free radical-mediated reactions might be responsible for some of the deleterious effects observed in actinically exposed skin is now accepted as fait accompli, it was at first received with due skepticism. Certainly, it had been clearly demonstrated that radicals resulted after UV radiation of excised skin (Pathak and Stratton, 1968). But the reason for this caution was based upon the fact that methodology required for rigorous testing for involvement of free radicals in pathogenesis had not advanced to the stage that lent itself well to in vivo measurement (Black, 1987). Thus, the gradual acceptance of free radical involvement in specific cutaneous disorders came largely from a considerable body of circumstantial evidence based upon indirect lines of investigation involving the major participants in such reactions, i.e., pro-oxidants, free radicals, and anti-oxidants. Examples include the amelioration of symptoms or a disease state by antioxidants, or the measurement of lipid oxidation. With respect to the former, it is becoming clear that antioxidant function is more complex, producing physiological responses that may or may not result from free radical scavenging. In addition, there are a number of pathologies where lipid oxidation has been shown to increase with no concurrent exacerbation of disease development and sometime to occur concomitantly with amelioration of the disorder (Rhodes et al, 1995). Thus, the relevance of these indirect responses to the pathology of specific disorders remains unclear. Recent advances in a number of analytical techniques, especially free radical spin trapping, have held promise to advance our knowledge of free radical roles in disease. Froncisz et al (1989) provided construction details, engineering characteristics, and spectroscopic performance data of a loop-gap resonator for the electron spin resonance (ESR) detection of spin labels. A low-frequency ESR spectrometer has been employed to measure free radical reactions in living mice (Utsumi et al, 1995). Free radical production in tissues of a living animal, the first report of such a direct measurement, employed lowfrequency paramagnetic resonance, in combination with in vivo spin trapping, to detect hydroxyl markers produced from ionizing radiation in the tumor of a living mouse (Halpern et al, 1995). He et al (2001), using a specially designed bridged loop-gap surface resonator, described in vivo imaging of free radicals in human subjects with the use of topically applied nitroxide spin labels and ESR. Using various oxygen-sensitive nitroxide spin labels and ESR, it was found that trap intensity corresponded to irradiance and penetration of UVB and UVA in human skin biopsies (Herrling et al, 2003). In this issue of the Journal, Takeshita and colleagues, in a carefully controlled study, have employed the griseofulvin-induced protoporphyria mouse model and in vivo ESR spectrometry to examine ROS generation and their potential role in this photosensitive disorder (2004). Although porphyrias may exhibit an indeterminate pattern of inheritance, they represent a group of diseases that result from deficiencies in specific enzymes in heme biosynthesis that takes place in the erythropoietic system and liver (Cox, 1997). Accumulation of heme precursors leads to a distinct syndrome of cutaneous photosensitivity, thought to result partly from photodynamic reactions of ROS with porphyrins (Buettner and Oberley, 1980). Edema and erythema occur within a few minutes after light exposure. The griseofulvin-induced protoporphyria mouse model has been thoroughly documented and is employed as a standard model for the study of Erythropoietic protoporphyria (Konrad et al, 1975). If, indeed, ROS produce damage associated with the photodynamic Abbreviations: DFO, desferr loxamine meystate; ESR, electron spin resonance; ROS, reactive oxygen species