This review considers recent advances in the chemical pathology of homocysteine in atherogenesis, oxidative metabolism, and carcinogenesis. Homocysteine is a potent excitatory neurotransmitter that binds to the N-methyl-D-aspartate (NMDA) receptor and leads to oxidative stress, cytoplasmic calcium influx, cellular apoptosis, and endothelial dysfunction. According to the adsorption-induction theory, cytoplasmic calcium influx leads to depletion of cellular adenosine triphosphate (ATP) by reaction with cytoplasmic phosphate, leading to calcium apatite deposition. Oxidative stress is caused by failure of ATP synthesis and accumulation of reactive oxygen radicals, theoretically because of inhibition of thioretinaco ozonide function within mitochondria and endoplasmic reticulum. The toxicity of oxygen difluoride is theoretically explained by the displacement of ozone from thioretinaco ozonide, leading to inhibition of cellular respiration. Depletion of thioretinaco ozonide from cellular membranes is suggested to underlie the carcinogenic and atherogenic effects of fluoride and other electrophilic carcinogens. In atherogenesis the acute inflammatory response is related to cellular apoptosis and necrosis, autoantibodies to proteins containing peptide-bound homocysteine and oxidized low-density lipoprotein (Ox-LDL), and microbial products and antigens originating from homocysteinylated LDL aggregates trapped within vasa vasorum of developing atherosclerotic plaques. The trapping of lipoprotein aggregates and obstruction of the lumen of vasa vasorum are enhanced by high tissue pressure and by endothelial dysfunction because of narrowing of the lumen by swollen and hyperplastic endothelial cells, leading to the creation of vulnerable plaques.
*Original abstract online at https://pubmed.ncbi.nlm.nih.gov/19667406/
Fluoride is a toxic anion that stimulates oxygen consumption  and increases superoxide production in resting polymorphonuclear leukocytes . Intracellular calcium ions are required for superoxide production by neutrophils during phagocytosis . The effect of fluoride on superoxide production in neutrophils is reversible, causing superoxide production in the presence of fluoride, decreasing superoxide production when fluoride is removed, and restoring superoxide production when fluoride is again added . Cellular viability is maintained during superoxide production. These experiments show that superoxide radical production by leukocytes is modulated by fluoride, providing a means for producing intracellular oxidative stress. In leukocytes, oxidative stress is an essential process by which phagocytosed microbes are inactivated and killed.
Fluoride has been known as a metabolic inhibitor for many years, causing inhibition of oxidative metabolism and decreased ATP synthesis . Fluoride is believed to inhibit the activity of many enzymes by disrupting the molecular structure of proteins by interfering with normal hydrogen bonding. In addition the effects of fluoride on chromosomal sturucture, genetic damage, and carcinogenesis may be attributable to inhibition of DNA repair enzyme structure . Fluoride forms unexpectedly strong hydrogen bonds in amide-fluoride systems, as determined by ab initio calculations and spectroscopic studies . The effect of fluoride inhibition of hydrogen bonding was determined by analysis of the threedimensional crystal structure of yeast cytochrome c peroxidase . These findings support the view that fluoride inhibits enzyme function by altering the conformation of the polypeptide backbone of proteins through interaction of peptidyl amide groups with fluoride .
The effect of fluoride in the induction of oxidant stress is attributable to interaction of fluoride ions with the amide groups of thioretinaco ozonide (Fig. 3). Conformational change in the binding of thioretinamide groups to the cobalt of thioretinaco by hydrogen bonding with fluoride would be expected to inhibit the binding of superoxide and other oxygen radicals to the active site of oxidative phosphorylation, resulting in inhibition of ATP synthesis and accumulation of oxygen radical species within cells.
In reviewing the toxicity of a selected series of gases formed from sulfur, nitrogen, fluorine, and carbon, pronounced differences are observed in the LC50 in experimental animals, as summarized in Table 2. The striking toxicity of oxygen difluoride, OF2, is in contrast to the other toxic gases in this group. This gas is toxic at concentrations two to three orders of magnitude less than all of the other examples in Table 2, with LC50 values of 2.6 ppm in rats and 1.5 ppm in mice. Nitrogen dioxide, NO2, and elemental fluorine, F2, have LC50 values of 100 to 185 ppm. Hydrogen sulfide, H2S, and hydrogen cyanide, HCN, have LC50 values of 713 and 544 ppm, respectively, in rats. The least toxic gas in this group is hydrogen fluoride, HF, with an LC50 of 1278 ppm in rats. For comparison, ethylene, CH2CH2, induces narcosis and has an LC50 of 950,000 ppm in mice.
Because of the extreme toxicity of oxygen difluoride, one of the most toxic gases known, this compound was investigated in World War I as a chemical weapon. The effectiveness of oxygen difluoride as a weapon is limited, however, by the decomposition of the compound in the presence of traces of water vapor or humidity in the atmosphere. This compound is suspected of causing injuries andbecause of its production from elemental fluorine and atmospheric oxygen in the synthesis of uranium hexafluoride .
As shown in Fig. 2, the molecular structure of oxygen difluoride is similar to that of ozone . Although the bond angle of oxygen difluoride, 103?18’, is more acute than that of ozone, 116?49’, the spacing of the two fluorine atoms, approximately 2.3 ?, is similar to the spacing of the two oxygen atoms about the central oxygen atom of ozone, approximately 2.2 ?. The reason is that the oxygen fluorine bonds of oxygen difluoride are slightly longer, 1.409 ?, than the oxygen oxygen bonds of ozone, 1.278 ?. The result of this bond configuration is that the central oxygen atom of oxygen difluoride is displaced from the plane of the fluoride atoms, approximately 0.9 ?, compared to the corresponding displacement of the central oxygen atom of ozone from the plane of the attached oxygen atoms,
approximately 0.7 ?. The oxidizing power of ozone is exceeded only by that of fluorine, atomic oxygen,
and OH radicals, and similar species .
The function of ozone in oxidative phosphorylation is considered to produce an active site with oxygen to form an oxygen ozone complex bound to the sulfonium centers of thioretinaco ozonide . This complex is suggested to bind
ATP synthesized by the F1 complex of ATPase of mitochondrial membranes from adenosine diphosphate and phosphate, as shown in Fig. 3. Because of its molecular structure and chemical reactivity, the extreme toxicity of oxygen difluoride is attributable to displacement of ozone from thioretinaco to form an inactive oxygen difluoride thioretinaco complex. Toxicity presumably results from inability of the oxygen difluoride complex to bind molecular oxygen or oxygen radicals, thereby preventing ATP synthesis. Thus the stereochemistry of the oxygen difluoride thioretinaco complex prevents binding of the alpha and gamma phosphates of ATP, inhibiting oxidative phosphorylation. Loss of ATP synthesis leads to cellular disintegration and decreased cellular viability because of loss of the high energy low entropy state of living cells .