Majid Ali, M.D.

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Editor, The Journal of Integrative Medicine
Formerly, Associate Professor of Pathology (adj.), College of Physicians
and Surgeons of Columbia University, NY
Formerly, President of Staff and Chief Pathologist, Holy Name Hospital, Teaneck, NJ
Fellow, Royal College of Surgeons of England - Diplomate,
American Board of Anatomic and Clinical Pathology
Diplomate, American Boards of Environmental Medicine
Past President Capital University of Integrative Medicine

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Oxygen's Love-Hate Relationships and the Dysox State
In the late 1990s, I introduced the term dysoxygenosis—dysox for short —for a state of dysfunctional metabolism characterized by disrupted oxygen signaling and impaired oxygen-driven cellular energetics.1-5 In Darwin, Dysox, and Disease, the tenth volume of The Principles and Practice of Integrative Medicine, I present Oxygen's Three-Legged Throne to describe at length certain aspects of the dysox state, as well as its clinical implications. Briefly stated, the three legs of oxygen's throne are: (1) acid-alkali balance; (2) oxidant- antioxidant regulation; and (3) clotting-unclotting dysequilibrium (CUD). These legs are weakened by the trio of toxic environment, toxic foods, and toxic thoughts. In this brief essay, I explain some basic aspect of oxygen-driven electron dynamics, which I designate as oxygen's "love- hate relationships with electrons."

Oxygen drives biology by its unique love-hate electron dynamics. A clear understanding of these relationships is essential for comprehension of the "oxygen funamentals." In this brif article, I offer somethings for general and professional readers.

Oxidation is a spontaneous process—it requires neither an expenditure of energy nor any outside cues. A flower wilts spontaneously; a wilted flower does not "unwilt" spontaneously. Fish rot spontaneously; rotten fish do not "unrot" spontaneously. Cut grass decomposes spontaneously; decomposed grass does not "undecompose" spontaneously. Thus, spontaneity of oxidation in nature is the natural phenomenon that provides the core mechanism of molecular injury in biology. Stated in another way, spontaneity of oxidation is nature's grand scheme to assure that no oxygen-utilizing form of life remains immune to the immutable law of oxidative death. Oxidation plays a similar role in the decay of inanimate matter as well. Iron rusts spontaneously; rusted iron does not "unrust" spontaneously. Reduction, the other side of the redox equation of life, requires expenditure of energy.

What is the energetic basis of spontaneity of oxidation in nature? A simple analogy may be used to answer this question. A boy is playing with a ball attached to a string. He keeps the ball flying in an orbit around him by moving his extended arm in a circle above his head. In this circumstance, the kinetic energy of the ball seeks to move the ball away from the boy, but it is counterbalanced by the pull of the string on it so that the ball stays in a circular orbit. If the boy lets go of the string, the ball will spontaneously fly away. The same thing would happen if the boy were to spin the ball with a greater force than can be sustained by the string. The above analogy may be completed by imagining that the ball moves in elliptical orbits—the string has extreme elasticity and pulls the ball closer to the boy's head by shrinking at one time and allows the ball to move far away from the boy by stretching at another time. (Physicists believe that atoms exist in a simultaneous particle-wave state determined by a particle-wave probability distribution.) A similar set of conditions governs the motion of electrons as they spin around the nucleus of an atom. Thus, spontaneity of oxidation (electron loss) is in reality a function of the kinetic energy of electrons that favors their outward movement, hence their loss. Thus no external source of energy is required in oxidation.

Electrons within atoms and molecules do not orbit the nucleus of an atom in the sense that the earth orbits the sun. Rather, electrons occupy regions of space called orbitals, which can hold no more than two electrons. A characteristic of electrons in a given orbital is that they demonstrate opposite spins. Within a molecule, two electrons sharing the same orbital exist in a bond called a covalent bond. A lone electron within an orbital is considered unpaired. This leads us to the definition of a free radical: any atomic or molecular species capable of an independent ("free") existence that contains one or more unpaired electrons in one or more orbitals.

Diatomic oxygen in ambient air is considered a radical because it contains two unpaired electrons. This structural characteristic of oxygen, according to thermodynamics, should allow oxygen to cause immediate combustion of all organic molecules that come in contact with it. Why does that not happen? The explanation is that the two unpaired electrons of diatomic oxygen in two different orbitals have the same spin quantum number. If oxygen were to directly oxidize organic molecules, it would have to accept two electrons from a donor with spins that are opposite to its own two unpaired electrons so as to be properly accommodated into the vacant spaces in oxygen's two orbitals containing unpaired electrons. This, of course, cannot be achieved by electrons in covalent bonds, which spin in opposite directions. Such spin restriction explains oxygen's poor reactivity even though it is a good oxidizer.* This explains why organic molecules do not spontaneously undergo combustion in oxygen. This also explains why glucose in oxygen, like ATP in water, is kinetically stable even though it is thermodynamically unstable. For oxygen to be reduced, it requires a paramagnetic catalyst such as heme iron or a copper chelate, which scrabble, so to speak, the electron spin in the donor.

More than 90% of the oxygen used in the human body is utilized by mitochondrial cytochrome oxidase, which transfers four electrons into an oxygen molecule to produce two molecules of water:

O2 + 4H+ + 4e- = 2H2O

Diatomic oxygen accepts electrons more efficiently than other electron acceptors such as NO3-, CO2 and SO42-, and to organic compounds such as NAD+ and quinones.

Under ordinary circumstances, reduction of oxygen by cytochrome oxidases in the above reaction does not release reactive oxygen radicals. This is assured by transitional metal ions such as iron, copper, vanadium and titanium, which are carried in the active sites of cytochrome oxidases. Such metal ions occur in variable states of oxidation, and changes in such states facilitate transfer of single electrons in an orderly fashion in which various partially reduced forms of oxygen are held bound to the metal ions. These ions also play essential roles in spontaneous oxidation (autoxidation) of several nonradical compounds including ascorbic acid; thiols such as cysteine, homocysteine and reduced glutathione; catecholamines such as epinephrine and norepinephrine; and a host of amines such as 3,4-dihydroxyphenylalanine (DOPA) and 6-hydroxydopamine.

Molecular oxygen has an interesting "love-hate" relationship with electrons. It avidly picks up free electrons in its vicinity, then just as avidly spins them out. In a vacuum, electrons travel at the speed of light. Even though the speed of an electron in tissues would be expected to be drastically reduced, the electron-oxygen transactions must still take place at amazingly fast speeds. During oxidative phosphorylation in the generation of ATP, molecular oxygen accepts an electron—is reduced—to become superoxide. Superoxide then loses its electrons spontaneously—is oxidized—in initiating the free radical chain reactions that result in the formation of peroxides, oxyacids, aldehydes and hydroxyl radicals. Such free radicals oxidize proteins of coagulation cascades, thus triggering oxidative coagulopathy, which further fans the fires of AA oxidopathy. However, our high-resolution microscopic observations described in this article lead us to conclude that accelerated oxidative stress on components of circulating blood is neither confined to oxidative injury of coagulation pathways nor, indeed, are the coagulative phenomena the initial events. We introduce the term AA oxidopathy to encompass a broad range of oxidative events that include: 1) peroxidation of plasma and cell membrane lipids; 2) oxidative permutations of plasma and cell membrane sugars and proteins; 3) accelerated autoxidation of nonenzymatic plasma antioxidants such as thiols and ascorbic acid; 4) inactivation or saturation of plasma enzymatic antioxidant mechanisms; 5) endothelial injury; and 6) later oxidative injury to subendothelial collagen and the muscularis of the arterial wall. Oxidative modification of LDL cholesterol—widely believed to be the critical event in atherogenesis—is, in our view, a relatively less significant event. We return to this essential issue later in this paper.

It may be pointed out that carbon- and sulfur-centered radicals generally react with oxygen with greater affinity than others included in the table given below.

1. Ali M, Ali O: AA oxidopathy: the core pathogenic mechanism of ischemic heart disease. J Integrative Medicine 1997;1:6-112.
2. Ali M: Oxidative regression to primordial cellular ecology. J Integrative Medicine 1998; 2:4-55.
3. Ali M: Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine 1999;3:11- 16.
4. Ali M: Fibromyalgia: an oxidative-dysoxygenative disorder (ODD). J Integrative Medicine 1999; 3:17-37.
5. Ali Recent advances in integrative allergy care. Current Opinion in Otolaryngology & Head and Neck Surgery 2000;8:260-266.
6. Ali M. Oxidative coagulopathy in environmental illness. Environmental Management and Health. 2000;11:175-191.
7. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. August/Sept. issue. 64-65.