Invited Review Free radical biology and medicine: it’s a gas, man!

an unactivated hydrogen atom at room temperature, and HO reacts with most of the species it collides with at a rate constant very near the diffusion limit. Superoxide can lead to the production of hydrogen peroxide, which is found in human fluids and exhaled breath (128, 133, 222, 232) but can be toxic. Hydrogen peroxide and superoxide may be separately regulated and, although each can cause pathological damage, both also function in normal cell regulation and signaling (48, 109, 196, 217, 218, 225). The interaction of superoxide-producing systems with iron is important in understanding superoxide chemistry, and we spend some time on this system. † Deceased June 13, 2005. Address for reprint requests and other correspondence: W. A. Pryor, Thomas and David Boyd Professor, Biodynamics Institute, Louisiana State Univ., Baton Rouge, LA 70803 (E-mail: [email protected]; [email protected]). Am J Physiol Regul Integr Comp Physiol 291: R491–R511, 2006. First published April 20, 2006; doi:10.1152/ajpregu.00614.2005. 0363-6119/06 $8.00 Copyright © 2006 the American Physiological Society http://www.ajpregu.org R491 by 10.0.33.6 on A uust 9, 2017 http://ajpphysiology.org/ D ow nladed fom We also discuss NO, peroxynitrous acid, and its conjugate base, peroxynitrite. Nitric oxide, a stable free radical, is a hormone-like species that contains no carbon atoms. (This remarkable discovery was recognized in 1998 with the award of a Nobel Prize to Robert Furchgott, Louis Ignarro, and Ferid Murad.) Peroxynitrite ( O-O-NAO) is formed by the combination of the two radicals, superoxide (O2 ) and nitric oxide ( NO). Peroxynitrite mediates some of the physiology and toxicity of nitric oxide and by oxidation and nitration can lead to altered protein function. In addition, carbon dioxide is a modulator of the biochemistry of peroxynitrite. This reaction begins as an addition of the peroxynitrite anion, O-O-NAO, to the CO2 molecule, forming an adduct, OAN-O-OC(AO)-O (135, 230). This species is unstable and rapidly decomposes to give nitrogen dioxide ( NO2) and the carbonate radical (CO3 ). We also discuss nitrogen dioxide, long studied in smog, but also formed in vivo when nitric oxide is present. It has recently been emphasized (210) that the combination of nitrogen dioxide ( NO2) and superoxide forms peroxynitrate (O2N-O-O ), the conjugate base of peroxynitric acid (O2N-OO-H). There are two other forms of reactive oxygen: singlet oxygen, an excited form of oxygen in which all the electrons are paired, and ozone, O3, a nonradical that is a potent oxidant in photochemical smog. Ozone is known to greatly accelerate the air oxidation of biomolecules (50, 170, 178, 179, 182). We also discuss carbon monoxide and hydrogen sulfide, which have fundamental cell signaling properties and effect oxidative stress. There are other gases that either respond to, or directly affect, the level of radicals, oxidants, and oxidative stress. Included in the list are ethylene (13, 25, 183) and a number of others. Perhaps this account will encourage others to take up the biochemistry of these other gases. Our purpose here is to group together a discussion of these gases and to focus attention on the surprising fact that nature chose gases to perform vital biological functions involving oxidative stress. Free radical biology has often been controversial. The word “radical” itself may be part of the problem, evoking visions of unkempt men stirring up revolution in coffeehouses. Vitamin E, nature’s favorite antioxidant (19, 101), also has had a controversial history, since the original biodetection method, rat fetus resorption, led to the early association of vitamin E with human sexual function, despite the fact that vitamin E deficiency does not cause fetus resorption in mice, humans, or most other species. 1) Oxygen: Triplet And Singlet The electronic ground state of dioxygen is a triplet (O2). Since it has two unpaired electrons, both with the same spin, it also is a diradical. Pairing these electrons to give one with “up” spin and one “down” gives a singlet state (O2). This takes energy, and the singlet is 1 eV (23 kcal/mol or 94 kJ/mol) higher in energy than the ground state triplet. The triplet state of oxygen (its ground state), O2, acts as a diradical, a one-electron oxidant (albeit a fairly poor one), whereas singlet O2 acts as a more potent, often two-electron, oxidant that adds to bonds, undergoes ene reactions, and can insert into CH bonds. The nearly unique triplet ground state of oxygen occurs because the two highest energy electrons reside in identical * molecular orbitals. In such a case, the triplet state is lower in energy because electrons with the same spin cannot occupy the same region of space (the Pauli exclusion principle). Electrons with opposite spin, as in the singlet state, can occupy the same region of space, but because the electrons are closer together on average, repulsion between these electrons is greater, and so the singlet state is higher in energy than the triplet. Oxygen atoms are present in a variety of minerals, and oxygen is the most abundant element in the Earth’s crust (93). Triplet oxygen supports metabolism through respiration. In mammalian systems, oxygen binds to hemoglobin, a marvelously tuned carrier of oxygen; hemoglobin moves oxygen through the organism and uses cooperative binding to maximize uptake and release to tissues that require O2. When released, O2 is involved in a series of complex redox cycles, ultimately being reduced to water and giving ATP. Singlet oxygen is not produced by simple thermal processes from O2, but requires intervention of high energy molecules. Singlet oxygen can be produced by energy transfer from the excited triplet states of aromatic dyes, like Rose Bengal, and also by fullerenes. These reactions occur with little or no activation enthalpy; Diels-Alder reactions, ene reactions, and 2 2 cyclo-additions with electron-rich alkenes (D electron donor) are common singlet oxygen reactions, as shown in the three reactions below (reactions 1–3) (62).