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Oxygen Toxicity and Reactivity: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Paola Venditti.

For most living beings, oxygen is an essential molecule for survival, being the basis of biological oxidations, which satisfy most of the energy needs of aerobic organisms. Oxygen can also behave as a toxic agent posing a threat to the existence of living beings since it can give rise to reactive oxygen species (ROS) that can oxidise biological macromolecules, among which proteins and lipids are the preferred targets.

  • oxygen toxicity
  • reactive oxygen species (ROS)
  • Cytochrome oxidase

1. Oxygen Toxicity

For most living beings, oxygen is an essential molecule for survival, being the basis of biological oxidations which satisfy most of the energy needs of aerobic organisms. Although oxygen is vital for these organisms, it can also behave as a toxic agent and prove to be a threat to their existence. This inconsistent aspect of aerobic life was defined by Davies as the “paradox of aerobic life” [12][1]. Indeed, the organisms can survive in the presence of oxygen because they have developed an elaborate antioxidant defence system, adapting to the Earth’s oxidising atmosphere. However, this system is only adequate for the atmospheric oxygen pressure (approximately 156 mm Hg), and there is strong evidence that exposure to oxygen pressures higher than atmospheric ones causes severe damage.
The toxicity of oxygen was already known in the 1770s when Joseph Priestley, who discovered oxygen, together with but independently from Carl Wilhelm Scheele, compared its effect on the body to candle burning, observing that a candle burns out faster in oxygen than in air and wondering if “the animal powers be too soon exhausted in this pure kind of air” [13][2].
The deleterious consequences of breathing oxygen at elevated partial pressures were first recognised in the late 19th century. Paul Bert was the first to describe the toxic effects of hyperbaric oxygen on the central nervous system [14][3] and Lorrain Smith was the first to describe the effects on the lungs [15][4].
Another example of oxygen toxicity is the retinopathy of prematurity (ROP). In preterm infants, supplemental oxygen administration has been frequently used as a life-saving treatment since the 1780s [16,17][5][6] and, in the 1940s regular supplemental oxygen use was established for the preterm infant [18][7]. The spread of the practice of oxygen supplementation in preterm infants led to an epidemic of severe retinopathy of prematurity and blindness between the 1940s and 1950s. In 1942, the phenomenon of retrolental fibroblastic overgrowth [19][8] was described, and in 1950 the role of oxygen in the development of this new sudden blindness observed in preterm infants, which was called retrolental fibroplasia [20][9], now known as ROP, was defined. Several studies have established the role of hyperoxia in ROP [21,22,23][10][11][12].
The susceptibility of the human retina to hyperoxia is due to vasculature being not fully developed until the full term of gestation, and the photoreceptors developing after the small vessels. Excess oxygen leads to the destruction and arrest of the development of the neurovascular retina, followed by abnormal neovascularisation during the vulnerable retinal development stage [24,25][13][14].
Currently, more careful control of oxygen use (continuous monitoring, with intermittent supplementation of O2, provided only to maintain blood O2 levels) has significantly decreased the severity of retinopathy [26][15]. Administration of the antioxidant α-tocopherol to preterm infants may reduce ROP but has been shown to have harmful effects in very preterm babies [27][16]. Nowadays, the use of vitamin E in the prevention of the exacerbation of ROP, and of other dysfunctions related to preterm, could be reconsidered in the light of current knowledge in the field of modern neonatal medicine [28][17].
High partial pressures of oxygen can also be harmful to adult humans due to their effects on the central nervous system, lungs, and eyes, even if other systems can also be affected [29][18]. The partial pressure of oxygen in inspired air, at the sea level, is about 160 mm Hg. This value can be increased by either breathing 100% oxygen, or by increasing the pressure of the breathing mixture [30][19]. These conditions can occur using hyperbaric oxygen for therapeutic purposes, or during underwater diving.
The signs of oxygen toxicity are detectable in various tissues; however, the most worrying are those affecting the central nervous system and the lungs, which can be considered real target organs.
The lungs’ sensitivity to the high partial pressure of O2, or a high percentage of oxygen in the breathing air, may be due to their greater exposure to high oxygen levels compared to other tissues in the body [29][18].
The pulmonary oxygen toxicity onset is directly related to the partial pressure of inspired oxygen, and usually, it does not occur at oxygen concentrations lower than 50% in young healthy subjects [31][20]. Pulmonary toxicity occurs after 4–22 h at an oxygen percentage greater than 95% at atmospheric pressure and within 3 h at 100% oxygen at 2–3 times the atmospheric pressure [32][21]. The first manifestation of pulmonary toxicity is tracheobronchial irritation associated with cough and progressive dyspnoea in men exposed to 98% oxygen for 30–74 h [33][22]. Longer exposures to oxygen may induce diffuse alveolar damage characterised by clinical symptoms and pathological signs of alveolar damage, like those of acute respiratory distress syndrome from other causes [34][23]. Prolonged exposure to sublethal concentrations of oxygen may result in chronic pulmonary fibrosis and emphysema with tachypnoea as well as progressive hypoxaemia that can cause, after a few days, lung damage so severe it may, paradoxically, cause death from anoxia [35][24].
Central nervous system (CNS) toxicity occurs following short-term exposure to air containing highly concentrated oxygen at a pressure above atmospheric. Exposure for minutes to hours at 160 kPa of partial pressure, approximatively eight times the atmospheric concentration, is generally associated with CNS toxicity [29][18]. CNS toxicity does not occur during normobaric exposure to high O2 concentrations, and conditions related to CNS toxicity can only be met in special situations such as immersion or hyperbaric oxygen treatment. The appearance time of the CNS toxicity initial symptoms (tunnel vision, tinnitus, nausea, facial twitching, dizziness, and confusion) is inversely related to the oxygen pressure and may be as short as 10 min at pressures of 4–5 atmospheres absolute [32][21]. Initial symptoms may be followed by tonic-clonic seizures and subsequently by unconsciousness. The onset of the initial disturbances does not follow a defined pattern before the onset of the seizures, which are the most dramatic and dangerous symptom of oxygen toxicity. However, the latter is reversible and leaves no neurological damage if the partial pressure of the inspired oxygen is reduced. The onset of seizures depends on the partial pressure of oxygen and the duration of exposure [29][18]. Moreover, the exposure time at which symptoms begin depends on many factors and can change in the same individual day by day [30,31][19][20].
Many factors such as underwater activity, cold weather, and physical activity can reduce the time to onset of CNS symptoms [29][18]. Oxygen toxicity is very dangerous during diving as it may cause drowning due to an epileptic attack. Understanding that a diver exhibits symptoms of oxygen toxicity is difficult before seizure activity develops, as the first symptoms are non-specific and do not follow a typical sequence.

2. Oxygen Reactivity

The toxicity of oxygen was initially attributed to its ability to inhibit cellular enzymes [36,37][25][26]. There are several examples of oxygen-mediated enzymatic inactivation in anaerobic organisms [38][27]. However, most enzymes in aerobic cells are insensitive to oxygen and those that are inactivated are poorly sensitive. Furthermore, the rate at which oxygen-sensitive enzymes are inactivated is too low and does not match the rate at which the toxic effects develop [1][28].
Subsequently, oxygen toxicity was attributed to the formation of oxygen radicals [39][29]. Despite being a free radical, O2 does not have high reactivity. The reactions in which it is involved do not take place at ordinary temperatures or in the absence of catalysts, even if its high oxidising power makes most of the substances of biological interest thermodynamically unstable in its presence [1][28].
The electronic configuration of diatomic oxygen explains this apparent contradiction. It has two unpaired electrons, each located in a different π* antibonding orbital [1][28]. The two electrons have the same quantum number of spins (they have parallel spins) in the ground state of oxygen. If oxygen attempts to oxidise another atom or molecule by accepting a pair of electrons from it, both electrons must have antiparallel spins to fit the empty space in the π* orbitals. However, a pair of electrons in an atomic or molecular orbital does not meet this criterion since they have opposite spins according to the Pauli principle. This represents a restriction (called a spin restriction) on the transfer of electrons to oxygen, which can accept electrons only one at a time. This explains why O2 reacts slowly with many non-radicals [39][29].
In aerobic organisms, the energy necessary for the vital processes derives from the oxidation reactions in which oxygen is consumed; therefore, it is evident that processes are operative in such organisms through which the spin restriction is, in some way, eliminated with a consequent increase in oxygen reactivity.
The elimination of the spin restriction could be achieved by putting enough energy in O2 to allow the inversion of the spin of one of its electrons in the π* orbital, thus passing O2 from the basal to an excited state named singlet oxygen. In the singlet oxygen, the elimination of the spin restriction makes oxygen much more reactive [40][30]. Moreover, the two electrons may remain in different orbitals or couple in one orbital. Therefore, two species with different reactivities are generated. Of the two singlet states of O2, the one with unpaired electrons has higher energy, truly short life in solution and decays quickly [41][31]. Differently, singlet oxygen with paired electrons has a much longer lifespan, so it is believed to be the only singlet oxygen species that react in solution [41][31].
The energy of light in the visible spectrum would be sufficient for the formation of singlet oxygen, but, fortunately, oxygen does not absorb visible light. The formation of singlet oxygen occurs when an appropriate dye, called a photosensitiser, absorbs visible light, and then collides with molecular oxygen transferring energy to it, giving rise to singlet oxygen [41][31]. There are many of these dyes in nature that support singlet oxygen formation. These include photosynthetic pigments, protoporphyrin IX (a heme precursor), Bengal rose, or methylene blue [41][31]. Singlet oxygen participates in many biochemical processes, such as photosynthesis, cell signalling, immune responses, or the degradation of polymers. However, the transformations are generally small and, therefore, cannot explain the evidence according to which many of the major changes occurring in cells consist of the O2 oxidation of various types of molecules.
Another way to avoid the spin restriction is to add electrons to oxygen one at a time, at a rate that allows for electronic rotational reversals between collision events [42][32]. The univalent oxygen reduction pathway requires the generation of oxygen reduction intermediates, which are reactive and can damage biological molecules [42][32].
These reactions are due to the intervention of substances that can transfer, in the right direction, one or more electrons from the molecule to be oxidised to O2 [1][28]. Among such substances, there are transition metal ions of varying valence, such as iron and copper, which have unpaired electrons with parallel spins and enzymes, such as cytochrome oxidase (Cox), which have metal ions in their active sites [1][28].
Cox is the terminal oxidase of cell respiration, accepts electrons from the reduced form of the cytochrome c (Cyt c), promotes the four-electrons reduction in oxygen to water, completes the electron transport of the mitochondrial respiratory chain, and can protect cells from the damage due to the formation of toxic intermediate of oxygen reduction [43][33]. In mammalian, Cox is a bigenomic enzyme. It contains 13 subunits, 3 catalytic subunits encoded by the mitochondrial genes and the remaining 10 encoded by the nuclear genome. The latter plays a role in the regulation and/or in the assembly of the enzyme. Cox contains two heme groups (heme a and a3) and two Cu2+ centres (Cu2+ A and Cu2+ B) in the catalytic centre and uses more than 90% of the oxygen consumed by cells and tissues [44][34].
Cox transforms O2 into the water in the reduction site that contains Fea3 and CuB, each of which accepts one electron. O2 bounds to the reduction site when both metals are in the reduced state (Fea32+ and CuB1+). The fully reduced state is named R-intermediate.
The bond of O2 to the R intermediate forms Fea33+–O2− (called intermediate A). This is converted into intermediate P without electron transfer from low-potential metal sites (Fea and CuA). When the P intermediate forms, the bound O2 accepts four electrons (two from Fea3, one from CuB, and the fourth from a neighbouring OH tyrosine). In the intermediate P, an oxide (O2−) and a hydroxide (OH−) bond to Fea3 and CuB, respectively. Subsequently, intermediate P receives four electrons from cytochrome c through the low potential metal sites, CuA and Fea (heme a). These equivalents are added one at a time, forming the intermediates F−, O−, and E, and finally reproducing the intermediate R. Each electron transfer from heme and couples with the pumping of one proton in the intermembrane space of the mitochondria, creating the driving force for ATP synthesis [43][33].
According to this view, the first three phases of the reaction generate, in sequence, the superoxide ion (O2•−), peroxide ion (O22−), which immediately protonates to hydrogen peroxide (H2O2), and the hydroxyl radical (•OH). The addition of the fourth electron leads to the hydroxyl ion, which is transformed into water by the addition of an H+.
Cox, firmly bound in its active site, holds all partially reduced intermediates of O2 until complete reduction.
These intermediates of oxygen reduction do not have the kinetic impediments of O2 in the ground state and are much more reactive. For this reason, they are referred to as reactive oxygen species (ROS).
However, Cox is not a site of ROS release in the cells. Several experimental pieces of evidence suggest that other cellular sites are responsible for the formation of ROS.
In the ROP, the ROS generated during the hyperoxia determines the destruction arrest of the development of the neurovascular retina as well as abnormal neovascularisation during a vulnerable developmental retinal stage [24,25][13][14].

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