Table 1.
Major host-derived cytotoxic agents and their antagonizing principles.
| Cytotoxic Agent | Mode of Cytotoxic Action | Antagonizing Principles | Remarks |
|---|---|---|---|
| Superoxide anion radical | Release of Fe2+ from [4Fe-4S]2+ clusters, formation of peroxynitrite | Superoxide dismutases, cytochrome c | |
| Hydrogen peroxide | Formation of hydroxyl radicals in reaction with Fe2+ or Cu+ | Catalase, peroxiredoxins, glutathione peroxidases | |
| Hydroxyl radicals | Diffusion-controlled oxidation of many substrates | No antagonizing principles; only limited protection by carbohydrates |
Prevention of their formation is the main strategy Very dangerous |
| Peroxynitrite | Formation of substrate radicals, nitration of tyrosine residues, initiation of lipid peroxidation | Myeloperoxidase, heme proteins | |
| Hypochlorous acid, hypobromous acid | Preferred oxidation of cysteine, methionine residues Interaction with aromatic amino acid residues and amino groups |
SCN−, taurine, glutathione (GSH), ascorbate | |
| Myeloperoxidase (MPO) | Formation of HOCl, HOBr, substrate radicals | Ceruloplasmin | |
| Free transition metal ions | Dangerous radical species in reaction with H2O2 and organic hydroperoxides | Proper control over all aspects of iron and copper ion metabolism | Enhanced yield of free transition metal ions is dangerous |
| Free methemoglobin | Formation of free heme | Haptoglobin | |
| Free metmyoglobin | Formation of free heme | Haptoglobin | |
| Free heme | Oxidation at hydrophobic loci, hemolysis of red blood cells, cytotoxic to kidney and liver, interaction with G4 structures in nucleic acids, can act as DAMP | Hemopexin Heme oxygenase |
Very dangerous |
| Oxidative products in lipid phases such as lipid peroxyl radicals and lipid hydroperoxides | Induction of further oxidative modifications of yet-unperturbed molecules | Lipid antioxidants such as α-tocopherol, carotinoids, ubiquinol, dehydrolipoic acid Glutathione peroxidase 4 (GPX4), and GSHProper control over transition free metal ions |
|
| Oxidative products in water-exposed molecules | Induction of further oxidative modifications of yet-unperturbed molecules | Urate, ascorbate, polyphenols Proper control over transition free metal ions |
|
| Neutrophil elastase | Cleavage of many extracellular matrix components, formation of angiotensin II | α1-antitrypsin (A1AT), secretory leukocyte protease inhibitor (SLPI), elafin, serpin B1, α2-macroglobulin | Failure of anti-proteases to inhibit elastase at severe oxidative stress Very dangerous |
| Cathepsin G | Cleavage of extracellular matrix components, receptor shedding, formation of angiotensin II | A1AT, α1-antichymotrypsin, SLPI | |
| Proteinase 3 | Cleavage of extracellular matrix components, in particular elastin | A1AT, elafin | |
| Mast cell tryptases | Cleavage of extracellular matrix components | Heparin-binding proteins such as lactoferrin, MPO, antithrombin III | Protected by heparin against the action of anti-proteases |
| Mast cell chymase | Cleavage of extracellular matrix components, chemokines, and cytokines, formation of angiotensin II | α1-antichymotrypsin | |
| Angiotensin II | Receptor-mediated pro-inflammatory effects | Angiotensin converting enzyme 2 (ACE2) | Very dangerous |
| Bradykinin | Receptor-mediated pro-inflammatory effects | Aminopeptidase P, angiotensin converting enzyme (ACE) | |
| Matrix metalloproteases (MMPs) | Cleavage of extracellular matrix components | Tissue inhibitors of metalloproteases (TIMPs) | Problems at shifted balance between MMPs and TIMPs |