Detoxification of hydrogen sulfide by synthetic heme model compounds

Abstract

Abstract Hydrogen sulfide is a lethal toxic gas that disrupts cellular respiration in the mitochondrial system. Currently, no antidote is available for the clinical treatment of hydrogen sulfide poisoning. In this study, we investigated the function of iron(III)porphyrin complexes as hydrogen sulfide scavengers in water and evaluated their potential use as therapeutic agents for hydrogen sulfide poisoning. The compounds, named met-hemoCD-P and met-hemoCD-I, are composed of iron(III)porphyrin complexed with per-methylated β-cyclodextrin dimers that contain a pyridine (met-hemoCD-P) or imidazole axial fifth ligand that is coordinated to Fe(III) (met-hemoCD-I). These compounds formed stable HS–Fe(III) complexes under physiological conditions, with binding constants of 1.2 × 105 and 2.5 × 106 M–1 for met-hemoCD-P and met-hemoCD-I, respectively. The binding constant of met-hemoCD-I was 10-times higher than that reported for native human met-hemoglobin at pH 7.4 and 25oC. Electron paramagnetic resonance (EPR) spectroscopy and H2S quantification assays revealed that after SH– was coordinated to met-hemoCD-I, it was efficiently converted to nontoxic sulfite and sulfate ions via homolytic cleavage of the HS–Fe(III) bond followed by aerobic oxidation. Mouse animal experiments revealed that the survival rate was significantly improved when NaSH-treated mice were injected with met-hemoCD-I. After the injection, mitochondrial CcO function in brain and heart tissues recovered, and met-hemoCD-I injected was excreted in the urine without chemical decomposition.

Keywords

• Hydrogen sulfide
• Heme
• Porphyrin
• Cyclodextrin
• Injectable antidote