Reactions of melatonin with oxidants


With regard to the presence of melatonin in food, in medicinal plants and to the use as a food additive, its antioxidant and other protective properties deserve attention. Since the discovery of melatonin oxidation by photocatalytic mechanisms involving free radicals [15,44,45], scavenging by this indoleamine has become a matter of particular interest. Melatonin was also shown to be oxidized by free radicals formed in the absence of light [46], and its capability of scavenging hydroxyl radicals at high rates [47-51] initiated numerous investigations on radical detoxification and antioxidative protection. Melatonin turned out to be considerably more efficient than the majority of its naturally occurring structural analogs [47,50-52], indicating that the substituents of the indole moiety strongly influenced reactivity and selectivity. Rate constants determined for the reaction with hydroxyl radicals were in the range between 1.2 × 1010 and 7.5 × 1010 M-1 s-1, depending on the methods applied [53-57]. Regardless of differences in the precision of determination, melatonin has been shown, independently by different groups, to be a remarkably good scavenger of this radical species. This property can be crucial for antagonizing oxidative damage under pharmacological and other in vitro conditions. To what extent this may contribute to physiological protection remains, however, a matter of debate.

Meanwhile, melatonin has been shown to react with many other oxidants, such as carbonate radicals [58-60], singlet oxygen [15,34,61-65], ozone [15,34], and several biologically occurring aromatic radicals, such as protoporphyrinyl and substituted anthranilyl radicals [15,59,61,62,66,67]. Reactions with other non-biological radicals were also described [15,34], among which the ABTS cation radical [ABTS = 2, 2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)] merits special attention because of its analytical value. This extremely long-lived radical which is stable for many days provides a good example for single-electron donation by melatonin [52,68]. This conclusion was unambiguously confirmed by cyclic voltammetry [69]. Single-electron donation is important for several reasons. Free radicals can react with scavengers in different ways, either by abstraction of an electron, or a hydrogen atom, or by addition. In the case of melatonin, radical addition has been observed or predicted theoretically only for interactions with hydroxyl radicals [69-72] and nitric oxide [69,73-75]. Electron/hydrogen abstraction, however, is a common key step for interactions of melatonin with oxidizing free radicals of both high and low reactivity and, therefore, reflects melatonin's property as a broad spectrum antioxidant. Electron abstraction was also concluded to be a primary step of melatonin oxidation in a pseudoenzymatic reaction catalyzed by oxoferrylhemoglobin [76]. Single-electron transfer reactions are also believed to play a role in detoxification of resonance-stabilized free radicals, such as carbonate and aryl radicals, which are frequently underrated in their destructive potential because of their lower reactivity, compared to the hydroxyl radical. However, due to their longer life-time they can reach more distant sites than the extremely short-lived hydroxyl radical, which exists only for nanoseconds. The capability of melatonin of scavenging carbonate and certain aryl radicals may be of much higher significance and protective value than previously thought. Finally, according to a recently proposed model, single-electron exchange is thought to be the basis for interactions of melatonin with the mitochondrial respiratory chain [77,78] which is assumed to require only very small, quasi-catalytic amounts of melatonin and which would convey antioxidative cell protection by radical avoidance rather than detoxification of radicals already formed (see below).

Reactive nitrogen species represent another category of potentially destructive substances, which react with melatonin. Scavenging of nitric oxide by melatonin in a nitrosation reaction is well documented [9,79-81]. Whether this can be regarded as a detoxification reaction keeping nitric oxide from forming the more dangerous peroxynitrite is uncertain because nitrosomelatonin easily decomposes, thereby releasing nitric oxide [82], an experience also made with other nitric oxide adducts from respective scavengers including nitric oxide spin traps [83]. Scavenging of peroxynitrite has also been described [9,80,81,84], although it is sometimes difficult to distinguish betweeen direct reactions with peroxynitrite and with hydroxyl radicals formed by decomposition of peroxynitrous acid. What seems more important than direct scavenging of peroxynitrite is the interaction with products from the peroxynitrite-CO2 adduct (ONOOCO2-), namely, carbonate radicals (CO3•-) and •NO2 [79,85]. In the presence of bicarbonate/CO2, this pathway is favored and the primary interaction of melatonin is that with CO3•- [85], a conclusion in agreement with results from other studies on CO3•- scavenging [58-60]. The mixture of CO3•- and •NO2 represents the physiologically most efficient nitration mixture, because of the high availability of CO2 in biological material. It is worth noting that melatonin can, in fact, decrease 3-nitrotyrosine levels, as shown in guinea pig kidney [86].

Another highly interesting aspect of melatonin's antioxidant actions, which may be particularly important from the nutritional aspect, is its interactions with classic antioxidants. In both chemical and cell-free systems, melatonin was repeatedly shown to potentiate the effects of ascorbate, Trolox (a tocopherol analog), reduced glutathione, or NADH [50,68,69,87]. These findings, which can be clearly distinguished from additive effects, surprisingly indicate multiple interactions via redox-based regeneration of antioxidants transiently consumed. This may, in fact, be of practical importance, since melatonin was also shown to prevent decreases in hepatic ascorbate and a-tocopherol levels in vivo, under conditions of long-lasting experimental oxidative stress induced by a high cholesterol diet [88].

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