Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases
Abstract
:1. Introduction
2. The Properties and Role of Iron and Iron Proteins in Human Health
2.1. Basic Properties and Distribution of Iron in the Body
2.2. Iron in Heme, Hemoglobin and Red Blood Cells
2.3. The Role and Function of Iron-Containing Proteins
2.4. Factors Affecting Iron-Containing Proteins and Implications on Health
3. Ligands and Chelators Binding with Iron
3.1. Naturally Occurring Microbial Chelators (Siderophores)
3.2. Naturally Occurring Plant Chelators (Phytochelators)
3.3. Iron Chelating Drugs in Clinical Use
4. Biologic and Physiological Implications of Interactions with Iron Chelators
4.1. Effects of Chelator and Chelator Iron Complexes on Iron Absorption
4.2. Iron Removal by Chelators from Ferritin and Hemosiderin and Other Proteins
4.3. Transferrin Iron Removal and Other Interactions by Chelators
4.4. The Intracellular Low Molecular Weight Iron Pool Changes during Chelation
4.5. Allosteric and Other Interactions of Chelating Drugs with Proteins
5. Interaction of Iron Proteins with Other Metal Ions and the Role of Chelators
6. Chelator Protein Interactions and Free Radical Pathology
7. Prospects for the Clinical Use of Chelators in Infections and Cancer
7.1. Iron, Chelation and Therapeutic Strategies in Infections
7.2. Iron, Chelation and Cancer Therapeutic Strategies
8. Future Prospects
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Protein | Iron Complex Prosthetic Group | Function |
---|---|---|
Hemoglobin | Heme | Oxygen transport |
Myoglobin | Heme | Oxygen transport |
Cytochromes | Heme | Electron transport. Respiration |
Cytochrome P450 | Heme | Drug detoxification |
Ribonucleotide reductase | Amino acids | DNA synthesis |
Proline hydroxylase | Amino acids | Collagen synthesis |
Phenylalanine hydroxylase | Amino acids | Degradation of phenylalanine |
Tryptophan 2,3-dioxygenage | Heme | Degradation of tryptophan |
Homogentisic acid 2,3-dioxygenase | Amino acids | Detection of alkaptonuria |
Peroxidases | Heme | Decomposition of hydroperoxides |
Catalase | Heme | Decomposition of hydrogen peroxide |
Lipoxygenase | Amino acids | HPETE and leukotriene synthesis |
Cyclooxygenase | Heme and Amino acids | Prostaglandin and thromboxane synthesis |
Adrenodoxin | 2Fe-2S | Electron transport. Oxidation/reduction |
Aconitase | 4Fe–4S | Tricarboxylic acid cycle |
Succinate dehydrogenase | 2Fe-2S, 4Fe–4S, 3Fe-4S | Tricarboxylic acid cycle |
NADH dehydrogenase | Fe–S Clusters | Electron transport. Respiration |
Xanthine oxidase | 4x (2Fe-2S) | Conversion of xanthine to uric acid |
Aldehyde oxidase | 2x (2Fe-2S) | Metabolism of aldehydes |
Transferrin | Amino Acids | Iron transport in plasma |
Lactoferrin | Amino Acids | Iron binding in milk and secretions |
Ferritin | Oxyhydroxide, phosphate Fe | Iron storage |
Hemosiderin | Oxyhydroxide, phosphate Fe | Iron storage |
Hephaestin | Not carrying or containing Fe | Ferroxidase and influx transmembrane iron transport |
Ferroportin | Not carrying or containing Fe | Efflux transmembrane iron transporter in cells |
Hepcidin | Not carrying or containing Fe | Regulatory protein affecting iron uptake and release |
Phosphates | Pyridoxal phosphate, thiamine pyrophosphate, ribonucleoside and deoxyribonucleoside phosphates, phytic acid (IP6), Pyrophosphate, ATP, ADP, AMP, etc. |
Amino acids | Aspartic acid, glutamic acid, histidine, cysteine, tyrosine, etc. |
Carboxylic acids | Citric acid, aconitic acid, oxaloacetic acid, etc. |
Mono- and di- saccharides | Fructose, glucose, lactose, etc. |
Vitamins | Ascorbic acid, lipoic acid, riboflavin. |
Fatty acids and phosphoglycerides | Oleic acid, linoleic acid, phosphatidic acid. |
Other naturally occurring chelators | Catecholamines, pteridines, purines, spermine, spermidine. Glutathione. Folic acid. |
Dietary molecules | In addition to food components containing the above molecules, there are also many plant products including most polyphenols and other phytochelators with iron chelating properties such as: gallic acid, caffeic acid, quercetin, ellagic acid, curcumin, catechin, maltol, etc. |
Ion | EDTA | DTPA | Deferoxamine | Deferiprone | Deferasirox |
---|---|---|---|---|---|
Fe3+ | 25.1 | 28.6 | 30.6 | 35.0 | 27.0 |
Cu2+ | 18.8 | 21.0 | 14.0 | 19.6 | – |
Zn2+ | 16.5 | 18.4 | 11.1 | 13.5 | – |
Charge | |||||
(pH 7) | −ve | −ve | +ve | neutral | −ve |
MWt | 292 | 393 | 561 | 139 | 373 |
Iron oxidation | Oxidation of Fe (II) to Fe (III) by L1, DFO or transferrin at pH 7.4 Oxidation of hemoglobin to methemoglobin by DFO Oxidation of cytochrome c by 2,3-dihydroxybenzoic acid |
Iron reduction | Heme Fe (IV) to Fe (III) in myoglobin and hemoglobin by DFO and L1 |
Allosteric interactions | L1 and hemoglobin. Hydroxyurea and ribonucleotide reductase. |
Competition with other metals | Order of stability constants of L1, DFO with metals: Fe>Al> Zn>Mg |
Lipid / water partition coefficients (Kpar: n-octanol/water) | Order of hydrophilicity: DTPA and EDTA >DFO>L1>DFRA Order of lipophilicity: 8-hydroxyquinoline >tropolone>maltol |
Inhibition or increase of iron induced free radical damage | L1 and DFO inhibit iron induced free radical damage to the DNA sugar deoxyribose. EDTA causes an increase in the iron induced free radical damage to deoxyribose. |
Inhibition of iron-containing enzymes by iron chelating drugs | Lipoxygenase and cyclooxygenase inhibition by L1 and DFO. Catechol-O-methyltransferase, tyrosine and tryptophan hydroxylase inhibition by L1. |
Promotion and inhibition of cell growth by iron binding and transport to cells | Maltol promotes cell growth. L1 and DFO inhibit cell growth. |
Iron donors to transferrin | Ascorbate, citrate and L1 bound iron. DFO bound iron is not available to transferrin. |
Iron mobilization from diferric transferrin and lactoferrin | L1 mobilizes iron preferentially from the C-terminal site and mimosine preferentially from the N-terminal site of transferrin. DFO and DFRA are not effective in transferrin or lactoferrin iron mobilization. |
Differential rate of mobilization of iron species and forms by L1 | Mononuclear> oligonuclear> polynuclear. Transferrin, lactoferrin > ferritin, hemosiderin. |
Increase in iron excretion and route of elimination in iron loaded patients | L1: Urinary iron. DFRA: Fecal iron. DFO: Urinary and fecal iron. |
Differential iron removal from various organs. Efficacy is dose related. | L1 preferential iron removal from the heart and DFRA from the liver. DFO from the liver and to lesser extent from the heart. L1 iron removal from focal iron deposits in the brain of patients with neurodegenerative diseases. |
Iron removal from diferric transferrin in iron loaded patients | About 40% at L1 concentrations > 0.1 mM, but not by DFO or DFRA. |
Iron redistribution | DFO and especially L1 redistribute iron from the reticuloendothelial system to the erythron in anemic rheumatoid arthritis patients. DFO in cell studies. DFRA may cause redistribution of iron from the liver to other organs in thalassemia and other iron loaded patients. |
Increase excretion of metals other than iron, e.g., zinc (Zn) and aluminum (Al). | DTPA > L1 > DFO. (Order of increased Zn excretion in iron loaded patients). DFO and L1 cause increase Al excretion in renal dialysis patients. DFRA causes Al and other xenobiotic metal absorption. |
Iron mobilization and excretion of chelator metabolite iron complexes | Several DFO metabolites have iron chelation potential and cause increase in iron excretion. No increase in iron excretion by the L1 glucuronide and DFRA glucuronide metabolites. |
Combination chelation therapy | L1 and DFO or L1 and DFRA or other chelator combinations are likely to be more effective than monotherapy. |
Chelating drug synergism with reducing agents | Ascorbic acid acts synergistically with DFO, but not with L1 or DFRA for increasing iron excretion. |
Effects on iron absorption by lipophilic and hydrophilic chelators | Increase of iron absorption by maltol, 8-hydroxyquinoline and DFRA. Decrease of iron absorption by DFO, DTPA, EDTA and L1. |
Chelating drugs minimizing toxicity of other drugs | L1 and ICRF187 (Dexrazoxane), but not DFRA, inhibit doxorubicin induced cardiotoxicity. |
Chelator prodrugs | ICRF 187 (Dexrazoxane) is converted in vivo to an EDTA like chelator. |
Chelators with enterohepatic circulation | DFRA and cholyl hydroxamic acid. |
Deferiprone (L1) | Deferasirox (DFRA) | |
---|---|---|
Molecular Differences | ||
Molecular weight of chelators | 139 | 373 |
Molecular weight of iron complexes | 470 | 798 |
Charge of chelators at pH 7.4 | Neutral | Negative |
Charge of iron complexes at pH 7.4 | Neutral | Negative |
Partition coefficient of chelators (Kpar: n-octanol/water) | 0.19 | 6.3 |
Partition coefficient of iron complexes (Kpar: n-octanol/water) | 0.05 | Not reported |
Stability constant (Log K) of chelator iron complexes– (Transferrin: 36 ) | 35 | 27 |
Metabolic and Pharmacokinetic Differences | ||
Metabolite(s) | Glucuronide conjugate, which is cleared through the urine and have no iron chelation properties | Glucuronide conjugate cleared through the fecal route |
T1/2 absorption | 0.7–32 min | estimated within 1 h |
T max of the chelator | Mostly within 1 h | 1–3 h |
T1/2 elimination of chelator | 47–134 min at 35–71 mg/kg | 19 +/− 6.5 h at 20 and 40 mg/kg |
T1/2 elimination of the iron complex | Estimated within 47–134 min | 17.2 +/− 7.8 h at 20 mg/kg and 17.7 +/− 5.1 h at 40 mg/kg |
T max of the iron complex | Estimated within 1 h | at 20 mg/kg 1–6 h and at 40 mg/kg 4–8 h |
T max of the metabolite | glucuronide: 1–3 h | glucuronide: Not known |
Route of elimination of chelator and its iron complex | urine | Almost exclusively in feces and less than 0.1% of the administered dose in urine |
Enterohepatic re-circulation | L1 and iron complex not shown or suspected | DFRA and iron complex suspected from pharmacokinetic data |
Clinical Use and Dose Ranges | ||
Longest period of treatment | 33 years | 11 years |
Time of experience of clinical use | 33 years | 16 years |
Maximum dose in humans in 24 h | 250 mg/kg | 80 mg/kg |
Maximum iron excretion in 24 h | 325 mg | 55 mg (estimated from the reported iron balance studies using 40 mg/kg ) |
Dose in current use in 24 h | 75–110 mg/kg in divided doses | 20–40 mg/kg single dose |
Effective dose for iron balance in most thalassemia patients | >80 mg/kg/day | >40 mg/kg |
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Kontoghiorghes, G.J.; Kontoghiorghe, C.N. Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases. Cells 2020, 9, 1456. https://doi.org/10.3390/cells9061456
Kontoghiorghes GJ, Kontoghiorghe CN. Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases. Cells. 2020; 9(6):1456. https://doi.org/10.3390/cells9061456
Chicago/Turabian StyleKontoghiorghes, George J., and Christina N. Kontoghiorghe. 2020. "Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases" Cells 9, no. 6: 1456. https://doi.org/10.3390/cells9061456