key: cord-274698-i3mzzxwq authors: Stief, Thomas W title: The physiology and pharmacology of singlet oxygen date: 2003-02-19 journal: Med Hypotheses DOI: 10.1016/s0306-9877(03)00026-4 sha: doc_id: 274698 cord_uid: i3mzzxwq Reactive oxygen species (ROS) are generated by many different cells. Singlet oxygen (1O2) and a reaction product of it, excited carbonyls (CO(*)), are important ROS. 1O2 and CO(*) are nonradicalic and emit light (one photon/molecule) when returning to ground state oxygen. Especially activated polymorphonuclear neutrophil granulocytes (PMN) produce large amounts of 1O2. Via activation of the respiratory burst (NADPH oxidase and myeloperoxidase) they synthesize hypochlorite (NaOCl) and chloramines (in particular N-chlorotaurine). Chloramines are selective and stable chemical generators of 1O2. In the human organism, 1O2 is both a signal and a weapon with therapeutic potency against very different pathogens, such as microbes, virus, cancer cells and thrombi. Chloramines at blood concentrations between 1 and 2 mmol/L inactivate lipid enveloped virus and chloramines at blood concentrations below 0.5 mmol/L, i.e. at oxidant concentrations that do not affect thrombocytes or hemostasis factors, act antithrombotically by activation of the physiologic PMN mediated fibrinolysis; this thrombolysis is of selective nature, i.e. it does not impair the hemostasis system of the patient allowing the antithrombotic treatment in patients where the current risky thrombolytic treatment is contraindicated. The action of 1O2 might be compared to the signaling and destroying gunfire of soldiers directed against bandits at night, resulting in an autorecruitment of the physiological inflammatory response. Chloramines (such as the mild and untoxic oxidant chloramine T(®) (N-chloro-p-toluene-sulfonamide)) and their signaling and destroying reaction product 1O2 might be promising new therapeutic agents against a multitude of up to now refractory diseases. The human redox state is a balanced system of pro-and anti-oxidants. The main cellular reactive oxygen species (ROS) are hydrogen peroxide ðH 2 O 2 Þ, superoxide anion ðO ÅÀ 2 Þ, hydroxyl radical ðHO Å Þ, and singlet oxygen ð 1 O 2 Þ. Singlet oxygen -in contrast to the other oxidants -is nonradicalic and excited, i.e. 1 O 2 or the reaction product of 1 O 2 with a C@C group, i.e. an excited carbonyl, emits 1 photon when returning to ground state oxygen (1) . Whereas the radicalic oxygen species are harmful for the organism, nonradicalic 1 O 2 is rather mild and untoxic for mammalian tissue. This mild oxidative character has been used for diagnostic purposes, such as the radiohalogenation of proteins (2) (3) (4) . ROS are generated by pro-oxidative enzyme systems or by redox-cycling of pro-oxidative compounds. Pro-oxidative enzymes are the NADPH-oxidase (5), myeloperoxidase (6) , NO-synthase (7, 8) , or the cytochrome P-450 chain (9) (10) (11) . Physiologic activation of these pro-oxidative enzymes results into the normal oxidative state. NADPH-oxidase is mainly found in polymorphonuclear leukocytes (PMN). The membranous NADPH-oxidase generates superoxide anions that dismute to hydrogen peroxide. H 2 O 2 can react with superoxide anions or with HOCl or chloramines to form the nonradicalic 1 O 2 (10, 11) . Since NADPH-oxidase is present in many (5), diverse cells seem to generate the signal/messenger 1 O 2 for inter-or intra-cellular signaling. 1 O 2 is a cell signal and messenger (12) (13) (14) : redox active agents regulate ion channel activity in animals and plants (15) . 1 O 2 activates large-conductance, Ca 2þ -activated (maxi) K þ channels (16): monochloramine ðNH 2 ClÞ -in contrast to Tau-Cl -is membrane permeating and at 3-30 lmol=L it increases outward currents more than 8-fold (17, 18) . 1 O 2 , generated by chloramine-T â (N-chloro-p-toluene-sulfonamide), also inactivates the Na þ currents from skeletal or heart muscle fibers, presumably by oxidation of methionine residues (19) (20) (21) . Chloramine-T â has also been shown to modulate dose dependently outward currents in rabbit atrial cells (22, 23) or potassium channels (24) (25) (26) (27) . Chloramine-T â is known to abolish inactivation of Na þ and K þ channels (28) (29) (30) (31) (32) (33) . Potential receptors for excited oxygen species/ light are cryptochromes (34) , that consist of flavin-and pteridine-prosthetic groups. Pteridines seem to interact with excited oxygen (35-37). Chloramine-T â is bactericidal (38, 39) . N-chloramines exhibit low toxicity and skin irritation and are superior to chlorhexidine in preventing the expansion of the normal skin flora in vivo (40) . Chloramine-T â is better than HOCl in inactivation of Staphylococcus aureus (41) and monochloramine is superior to N-chlorotaurine in inactivation of Mycobacterium terrae (42) . NaOCl shows higher activity than chloramine-T â against Bacillus subtilis spores, coat and cortex material was degraded by chloramine-T â (43) . Because of their untoxicity and antimicrobial power (44), chloramines -especially chloramine-T â -is used for disinfection of drinking water, dialysate, or ice cream machines (45) (46) (47) (48) . Chloramine T â is also a therapeutic drug for treating bacterial gill disease, a predominant disease of a variety of fish species (49) . However, chloramine-T â at 10 g/L (35 mM) has been shown to be ineffective as fungicide (50) . Chloramines are virucidal, too (51) (52) (53) (54) (55) (56) . Even such dangerous viruses as the Marburg virus (57), or the Ebola virus (58, 59) are inactivated by chloramines. Bhanja virus (60), lymphocytic choriomeningitis virus (61) , simian rotavirus (62), or poliovirus (63) (64) (65) are sensible to NaOCl/chloramines. Even replicating agents of the Creutzfeldt-Jakob disease show some sensibility to NaOCl (74, 75) . Poliovirus on whole hands is inactivated (reduction factor >100) by 35 mM chloramine T â (63, 67) . Coxsackievirus B3, adenovirus type 5, parainfluenza virus type 3 and coronavirus 229E are inactivated (reduction factor >1000) by a 100 mM chloramine-T â solution (68) . NaOCl inactivates HIV-1 (66, (69) (70) (71) (72) . The 1.5 mM NaOCl inactivated more than 10 000 fold HIV in serum and 7.5 mM more than 10 fold in blood (73) . Own experiments show that chloramine-T â at blood concentrations that are tolerable for normal hemostasis function inactivate the lipid enveloped model virus VSV (vesicular stomatitis virus): 1 mmol/L chloramine-T â inactivates 90% of added VSV, 2 mmol/L chloramine-T â inactivate 99% of added VSV, i.e. there seems to exist a narrow therapeutical window for 1 O 2 treatment of human infections by enveloped viruses. Intravenous infusions of 1-1.5 mmol/L (blood concentration) chloramine (chloramine-T â or the physiologic N-chlorotaurine) once a week for several weeks might be a potent treatment modality for infections with lipid enveloped viruses, such as human immunodeficiency virus (HIV) (74) . Singlet oxygen is tumoricidal (75) . In photodynamic therapy (PDT) high concentrations of singlet oxygen are generated by illumination of a photosensitizer, resulting in a cytostatic action of PDT (76, 77) . However, excessive oxidant concentrations are carcinogenic (78) (79) (80) (81) (82) . 1 O 2 mediates PMN adherence to the endothelium (12, 83, 84) and subsequently selective thrombolysis (10, 11) . 1 O 2 activates the complement cascade, transforming C5 into a C5b-like molecule (85) ; activation of the complement cascade results in increased PMN adhesion to endothelial cells (86, 87) . Since cholesterol is an inhibitor of 1 O 2 , the atherogenic action of cholesterol might be explained by insufficient thrombolytic capacity of a hypercholesterolemic individuum (10, 11, 88) . However, and according to Paracelsus (dosis sola venenum facit (only the dosage makes the poison)), high concentrations of chloramines can act toxic to normal tissue (89) . 3 mM monochloramine induced DNA breakage (90) . PMN are the main cells that use singlet oxygen as a weapon. They also dispose of an enzyme that reverses methionine oxidation -the methionine sulfoxide-peptide reductase (91) . Taurine-chloramine is the major chloramine generated in activated PMN as a result of the reaction between HOCl (92) and taurine, an abundant free amino acid in their cytosol (93) (94) (95) (96) . Also other plasma proteins react with hypochlorite to chloramines (97). HOCl ð25 lMÞ or NH 2 Cl ð10 lMÞ -but not Tau-Cl ð100 lMÞ -increase endothelial permeability (98) or epithelial cell injury (99) . NH 2 Cl, the reaction product of hypochlorite with ammonia (NH 3 ), seems to be more toxic than Tau-Cl (100, 101) . The 60 mM NH 2 Cl (about 10 times the concentration generated by activated PMN!) is ulcerogenic in rat stomachs, taurine application (1 ml 200 mM) attenuates the deleterious action of NH 2 Cl (102), NH 2 Cl induces apoptosis in gastric mucosa (103) . Tau-Cl selectively modulates the ability of dendritic cells to induce the release of IL-2 and IL-10 from T cells (104) . Tau-Cl inhibits monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 production in glioma cells (105) . Tau-Cl inhibits the production of NO and superoxide anions (106) (107) (108) (109) , prostaglandin E2 (110, 111) , interleukin 6, and tumor necrosis factor-a and it has been suggested that Tau-Cl may regulate the balance between protective, microbicidal and toxic effect of PMN, Tau-Cl at 0.1-0.3 mM inhibits interleukin-2 release of purified T cells (112) . Chloramines -in contrast to sodium chlorite -do not induce detectable hematologic (! methemogloblin) or hepatic (! elevation of serum alanine-amino-transferase) in African Green monkeys (113) . However, a chloramineinduced haemolysis and erythropoietin resistance occurred when the dialysate chloramine levels rose from <0.1 to 0.3 p.p.m. (about 1 mM) resulting in an increase in mean methaemoglobin of 23% and a 21% fall in mean haptoglobin during haemodialysis; only one patient with glucose-6-phosphate-dehydrogenase deficiency had Heinz bodies (114, 115) . Dogs treated with 1 mmol/L blood concentration of chloramine T â 3 times a week for several months did not show toxic side effects (116) . Singlet oxygen is a major agent generated by many different cell types, especially by neutrophil granulocytes. 1 O 2 is nonradicalic and emits light when returning to ground state oxygen. Like the gunfire of soldiers directed against bandits, 1 O 2 is both a signal and a weapon, directed against multiple pathogens -including microbes, virus, cancer cells, thrombi -and resulting in an autorecruitment of the physiological inflammatory response. Chloramines are stable chemical generators of 1 O 2 . N-chlorotaurine is an important physiological chloramine, for therapeutic purposes chloramine-T â seems to be a promising new therapeutic agent against a multitude of up to now refractory diseases. Chemiluminescence of ABEI-labelled IgG triggered by the N-chloramine-H 2 O 2 -p-iodophenol system Iodination of biological samples without loss of functional activity A universal and simple chloramine T version for hormone iodination Chloramine-T in high-specific-activity radioiodination of antibodies using N-succinimidyl-3-(trimethylstannyl) benzoate as an intermediate NADPH-oxidase: an update Singlet oxygen ((1)D(g)O(2)) as the principal oxidant in myeloperoxidase-mediated bacterial killing in neutrophil phagosome Endothelium-dependent relaxation, endothelium-derived relaxing factor and photorelaxation of blood vessels FAD and GSH participate in macrophage synthesis of nitric oxide Spectral charcterization of brain and macrophage nitric oxide synthases. Cytochrome P-450 like hemeproteins that contain a flavin semiquinone radical The antithrombotic factor singlet oxygen/light ð 1 O 2 =hmÞ The blood fibrinolysis/deep-sea analogy: a hypothesis on the cell signals singlet oxygen/photons as natural antithrombotics Activation of transcription factor AP-2 mediates UVA radiation-and singlet oxygen induced expression of the human intercellular adhesion molecule1 gene Current perspectives of singlet oxygen detection in biological environments Toxic and signaling effects of photochemically or chemically generated singlet oxygen in biological systems Redox agents regulate ion channel activity in vacuoles from higher plant cells Activation of the NF-jB transcription factor in a T-lymphocytic cell line by hypochlorous acid Monochloramine directly modulates Ca(2+)-activated K(+) channels in rabbit colonic muscularis mucosae Detachment of cultured cells from the substratum induced by the neutrophil-derived oxidant NH2Cl: synergistic role of phosphotyrosine and intracellular Ca 2þ concentration Oxidation of methionyl residues in proteins: tools, targets, and reversal Involvement of methionine residues in the fast inactivation mechanism of the sodium current from toad skeletal muscle fibers The activation gate of cardiac Na+ channel modulates voltage-and pH-dependent unbinding of disopyramide Modulation by chloramine-T of 4-aminopyridine-sensitive transient outward current in rabbit atrial cells The inactivation of sodium channels in the node of Ranvier and its chemical modification An endogenous inactivating inward-rectifying potassium current in oocytes of Xenopus laevis Modification of C-type inactivating Shaker potassium channels by chloramine-T Inactivation of the cloned potassium channel mouse Kv1.1 by the human Kv3.4 'ball' peptide and its chemical modification Modulation of voltagedependent inactivation of the inwardly rectifying K+ channel by chloramine-T Abolition with chloramine-T of inactivation in barnacle muscle fibers results in stimulation of the ouabain-insensitive sodium efflux Chloramine-T effect on sodium conductance of neuroblastoma cells as studied by whole-cell clamp and single-channel analysis Modification of electrophysiological and pharmacological properties of K channels in neuroblastoma cells induced by the oxidant chloramine-T Some properties of sodium channels in neuroblastoma cells modified with scorpion toxin and chloramine-T. Single channel measurements Irreversible modification of sodium channel inactivation in toad myelinated nerve fibres by the oxidant chloramine-T Removal of sodium channel inactivation in squid axon by the oxidant chloramine-T Cryptochromes: blue light receptors for plants and animals Effects of pteridines on chloramine-T-induced growth inhibition in E. coli strains: correlations with molecular structure Effects of pteridines on luminol-dependent chemiluminescence induced by chloramine-T. Free Radic A possible origin of chemiluminescence in phagocytosing neutrophils. Reaction between chloramines and H2O2 Evaluation of bactericidal activity and lag of regrowth (postantibiotic effect) of five antiseptics on nine bacterial pathogens Efficacy of a variety of disinfectants against Actinobacillus pleuropneumoniae serotype 1 Comparative antimicrobial activity, in vitro and in vivo, of soft N-chloramine systems and chlorhexidine Model tests for the efficacy of disinfectants on surfaces. IV. communication: dependence of test results on the amount of contamination and the kind of active substance Rapid killing of Mycobacterium terrae by N-chlorotaurine in the presence of ammonium is caused by the reaction product monochloramine Interaction of Bacillus subtilis spores with sodium hypochlorite, sodium dichloroisocyanurate and chloramine-T Neopterin derivatives modulate toxicity of reactive species on Escherichia coli Effect of monochloramine disinfection of municipal drinking water on risk of nosocomial Legionnaires' disease Erythropoietin resistance due to dialysate chloramine: the two-way traffic of solutes in haemodialysis Chloramine, a sneaky contaminant of dialysate Spectrodensitometric determination of chloramine-T in ice cream Liquid chromatographic determination of para-toluenesulfonamide in edible fillet tissues from three species of fish Fungicidal effect of 15 disinfectants against 25 fungal contaminants commonly found in bread and cheese manufacturing Inactivation of Lactobacillus helveticus bacteriophages by thermal and chemical treatments Inactivation of feline calicivirus, a Norwalk virus surrogate Inactivation of respiratory syncytial virus by detergents and disinfectants A surface test for virucidal activity of disinfectants: preliminary study with herpes virus Sodium hypochlorite in the treatment of herpes simplex virus infections Inactivation of coxsackieviruses B3 and B5 in water by chlorine Disinfecting action of chloramine B on Marburg virus The effect of some physical and chemical factors on inactivation of the Ebola virus Ebola virus: what the practitioner needs to know Some physical and chemical properties of Bhanja virus V. Influence of several chemical reagents on lymphocytic choriomeningitis and Tacaribe viruses Inactivation of simian rotavirus SA11 by chlorine, chlorine dioxide, and monochloramine Inactivation of poliovirus by chloramine-T Virucidal activity of disinfectants: studies with the poliovirus Inactivation of poliovirus I (Brunhilde) single particles by chlorine in water Cupric and ferric ions inactivate HIV Two in-vivo protocols for testing virucidal efficacy of handwashing and hand disinfection Chemical disinfection of non-porous inanimate surfaces experimentally contaminated with four human pathogenic viruses Mash D. C. Preliminary laboratory studies of inactivation of HIV-1 in needles and syringes containing infected blood using undiluted household bleach Evaluation of hypochlorite-releasing disinfectants against the human immunodeficiency virus (HIV) Chemical inactivation of human immunodeficiency virus in vitro Stability and inactivation of HTLV-III/LAV under clinical and laboratory environments Inactivation of HIV-1 by chemical disinfectants: sodium hypochlorite Singlet oxygen ð 1 O 2 Þ-generating chloramines at concentrations that are tolerable for normal hemostasis function inactivate the lipid enveloped vesicular stomatitis virus in human blood Efficacy of tumoricidal agents in vitro and in vivo Jr Photodynamic therapy: a review Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo Attenuation by methionine of monocloramine-enhanced gastric carcinogenesis induced by N-methyl-N 0 -nitro-N-nitrosoguanidine in Wistar rats Results of long-term carcinogenicity studies of chlorine in rats Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes Monochloramine induced DNA fragmentation in gastric cell line MKN45 Singlet molecular oxygen evolution upon simple acidification of aqueous hypochlorite: application to studies on the deleterious health effects of chlorinated drinking water Neutrophil-derived oxidants promote leukocyte adherence in postcapillary venules MPO) may mediate neutrophil adherence to the endothelium through upregulation of CD 11b expression -an effect downregulated by taurine Oxidants generated by the myeloperoxidase-halide system activate the fifth component of human complement, C5 Neutrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles for P-selectin and platelet activating activating factor Complement and atherogenesis: the unknown connection Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols Severe lung injury after exposure to chloramine gas from household cleaners Natural antioxidant, chlorogenic acid, protects against DNA breakage caused by monochloramine Human methionine sulfoxide-peptide reductase, an enzyme capable of reactivating oxidized a-1-proteinase inhibitor in vitro Mechanisms of hypochlorite injury of target cells Myeloperoxidase, hydrogen peroxide, chloride antimicrobial system: nitrogen-chlorine derivatives of bacterial components in bactericidal action against Escherichia coli Tissue destruction by neutrophils Oxidative regulation of neutrophil elastase-a-1-proteinase inhibitor interactions Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease Hypochlorite-induced oxidation of proteins in plasma: formation of chloramines and nitrogen-centred radicals and their role in protein fragmentation Hypochlorous acid and chloramines increase endothelial permeability: possible involvement of cellular zinc Taurine modulation of hypchlorous acid-induced lung epithelial cell injury in vitro. Role of anion transport Monochloramine-induced cytolysis to cultured rat gastric mucosal cells: role of glutathione and iron in protection and injury Effect of monochloramine on recovery of gastric mucosal integrity and blood flow response in rat stomachs -relations to capsaicin-sensitive sensory neurons Ulcerogenic and healing impairing actions of monochloramine in rat stomachs: effects of zinc L L -carnosine, polaprezinc Monochloramine-induced cell growth inhibition and apoptosis in a rat gastric mucosal cell line Regulation of murine dendritic cell functions in vitro by taurine chloramine, a major product of the neutrophil myeloperoxidase-halide system Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 production is inhibited by taurine chloramine in rat C6 glioma cells Preactivation exposure of RAW 264.7 cells to taurine chloramine attenuates subsequent production of nitric oxide and expression of iNOS mRNA Taurine chloramine inhibits the production of superoxide anion, IL-6 and IL-8 in activated human polymorphonuclear leukocytes Monochloramine inhibits phorbol ester-inducible neutrophil respiratory burst activation and T cell interleukin-2 receptor expression by inhibiting inducible protein kinase C activity The production of superoxide anion and nitric oxide by cultured murine leukocytes and the accumulation of TNF-a in the conditioned media is inhibited by taurine chloramine Taurine chloramine inhibits production of nitric oxide and prostaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclooxygenase-2 expression Taurine chloramine inhibits prostaglandin E2 production in activated RAW 264.7 cells by post-transcriptional effects on inducible cyclooxygenase expression Modulation of antigen-specific T-cell activation in vitro by taurine chloramine Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate Chloramine-induced haemolysis presenting as erythropoietin resistance A hemodialysis patient with chloramine-induced hemolysis. A discussion of the mechanism A model of decreased functional a-1-proteinase inhibitor. Pulmonary pathology of dogs exposed to chloramine T