14. CHEMICAL AND CLINICAL ASPECTS OF METAL-CONTAINING ANTIDOTES FOR POISONING BY CYANIDE
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Sigridur G. Suman
Abstract
Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme to execute metabolism of cyanide with minor pathways from other sulfurtransferases in vivo. The rhodanese enzyme depends on sulfur donor availability to metabolize cyanide and poisoning occurs at elevated cyanide concentrations in vivo. Cyanide interacts with over 40 metalloenzymes, but its lethal action is non-competitive inhibition of cytochrome c oxidase, halting cellular respiration and causing hypoxic anoxia. Only a handful of antidotes for treatment of cyanide poisoning are known; they are primarily inorganic compounds and metal complexes which are intended to intercept cyanide before it inhibits cellular respiration. The inorganic compounds manipulate hemoglobin, forming methemoglobin, or supply sulfur for the rhodanese enzyme. The metal complexes intercept the cyanide and bind it before reaching its target. Cobalt complexes of corrins and vitamin B12 derivatives are the state-of-the-art agents, while the longest employed complex, Co2EDTA, is designed to deliver “free” cobalt for binding of cyanide. Compounds that are in development are discussed from the point of how they are designed to intercept cyanide. The challenge of reversing the cyanide inhibition of cytochrome c oxidase is based on the catalytic active site structure and reactivity. General information about history and occurrence of poisoning and clinical symptoms is discussed and the challenges related to analytical methods available to analyze blood cyanide levels and to confirm the presence of cyanide poisoning.
Abstract
Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme to execute metabolism of cyanide with minor pathways from other sulfurtransferases in vivo. The rhodanese enzyme depends on sulfur donor availability to metabolize cyanide and poisoning occurs at elevated cyanide concentrations in vivo. Cyanide interacts with over 40 metalloenzymes, but its lethal action is non-competitive inhibition of cytochrome c oxidase, halting cellular respiration and causing hypoxic anoxia. Only a handful of antidotes for treatment of cyanide poisoning are known; they are primarily inorganic compounds and metal complexes which are intended to intercept cyanide before it inhibits cellular respiration. The inorganic compounds manipulate hemoglobin, forming methemoglobin, or supply sulfur for the rhodanese enzyme. The metal complexes intercept the cyanide and bind it before reaching its target. Cobalt complexes of corrins and vitamin B12 derivatives are the state-of-the-art agents, while the longest employed complex, Co2EDTA, is designed to deliver “free” cobalt for binding of cyanide. Compounds that are in development are discussed from the point of how they are designed to intercept cyanide. The challenge of reversing the cyanide inhibition of cytochrome c oxidase is based on the catalytic active site structure and reactivity. General information about history and occurrence of poisoning and clinical symptoms is discussed and the challenges related to analytical methods available to analyze blood cyanide levels and to confirm the presence of cyanide poisoning.
Chapters in this book
- Frontmatter i
- About the Editors v
- Historical Development and Perspectives of the Series vii
- Preface to Volume 19 ix
- Contents xiii
- Contributors to Volume 19 xix
- Titles of Volumes 1–44 in the Metal Ions in Biological Systems Series xxiii
- Contents of Volumes in the Metal Ions in Life Sciences Series xxv
- 1. METALS IN MEDICINE: THE THERAPEUTIC USE OF METAL IONS IN THE CLINIC 1
- 2. SMALL MOLECULES: THE PAST OR THE FUTURE IN DRUG INNOVATION? 17
- 3. IRON CHELATION FOR IRON OVERLOAD IN THALASSEMIA 49
- 4. IRONING OUT THE BRAIN 87
- 5. INFECTIONS ASSOCIATED WITH IRON ADMINISTRATION 123
- 6. IRON OXIDE NANOPARTICLE FORMULATIONS FOR SUPPLEMENTATION 157
- 7. BUILDING A TROJAN HORSE: SIDEROPHORE-DRUG CONJUGATES FOR THE TREATMENT OF INFECTIOUS DISEASES 181
- 8. DEVELOPING VANADIUM AS AN ANTIDIABETIC OR ANTICANCER DRUG: A CLINICAL AND HISTORICAL PERSPECTIVE 203
- 9. CHROMIUM SUPPLEMENTATION IN HUMAN HEALTH, METABOLIC SYNDROME, AND DIABETES 231
- 10. MANGANESE: ITS ROLE IN DISEASE AND HEALTH 253
- 11. COBALT-SCHIFF BASE COMPLEXES: PRECLINICAL RESEARCH AND POTENTIAL THERAPEUTIC USES 267
- 12. COPPER DEPLETION AS A THERAPEUTIC STRATEGY IN CANCER 303
- 13. METAL COMPOUNDS IN THE DEVELOPMENT OF ANTIPARASITIC AGENTS: RATIONAL DESIGN FROM BASIC CHEMISTRY TO THE CLINIC 331
- 14. CHEMICAL AND CLINICAL ASPECTS OF METAL-CONTAINING ANTIDOTES FOR POISONING BY CYANIDE 359
- SUBJECT INDEX 393
Chapters in this book
- Frontmatter i
- About the Editors v
- Historical Development and Perspectives of the Series vii
- Preface to Volume 19 ix
- Contents xiii
- Contributors to Volume 19 xix
- Titles of Volumes 1–44 in the Metal Ions in Biological Systems Series xxiii
- Contents of Volumes in the Metal Ions in Life Sciences Series xxv
- 1. METALS IN MEDICINE: THE THERAPEUTIC USE OF METAL IONS IN THE CLINIC 1
- 2. SMALL MOLECULES: THE PAST OR THE FUTURE IN DRUG INNOVATION? 17
- 3. IRON CHELATION FOR IRON OVERLOAD IN THALASSEMIA 49
- 4. IRONING OUT THE BRAIN 87
- 5. INFECTIONS ASSOCIATED WITH IRON ADMINISTRATION 123
- 6. IRON OXIDE NANOPARTICLE FORMULATIONS FOR SUPPLEMENTATION 157
- 7. BUILDING A TROJAN HORSE: SIDEROPHORE-DRUG CONJUGATES FOR THE TREATMENT OF INFECTIOUS DISEASES 181
- 8. DEVELOPING VANADIUM AS AN ANTIDIABETIC OR ANTICANCER DRUG: A CLINICAL AND HISTORICAL PERSPECTIVE 203
- 9. CHROMIUM SUPPLEMENTATION IN HUMAN HEALTH, METABOLIC SYNDROME, AND DIABETES 231
- 10. MANGANESE: ITS ROLE IN DISEASE AND HEALTH 253
- 11. COBALT-SCHIFF BASE COMPLEXES: PRECLINICAL RESEARCH AND POTENTIAL THERAPEUTIC USES 267
- 12. COPPER DEPLETION AS A THERAPEUTIC STRATEGY IN CANCER 303
- 13. METAL COMPOUNDS IN THE DEVELOPMENT OF ANTIPARASITIC AGENTS: RATIONAL DESIGN FROM BASIC CHEMISTRY TO THE CLINIC 331
- 14. CHEMICAL AND CLINICAL ASPECTS OF METAL-CONTAINING ANTIDOTES FOR POISONING BY CYANIDE 359
- SUBJECT INDEX 393
