Disulfides as Cyanide Antidotes: Evidence for a New In Vivo Oxidative Pathway for Cyanide Detoxification

Abstract

It is known that cyanide is converted to thiocyanate in the presence of the enzyme rhodanese. The enzyme is activated by sulfur transfer from an appropriate sulfur donor. The activated enzyme then binds cyanide and transfers the sulfur atom to cyanide to form thiocyanate. This project began as an exploration of the ability of disulfides to act as sulfur donors in the rhodanese-mediated detoxification of cyanide. To our surprise, and contrary to expectations based on efficacy studies in vivo, our in vitro results showed that disulfides are rather poor sulfur donors. The transfer of a sulfur atom from a disulfide to the enzyme must occur via cleavage of a carbon-sulfur bond either of the original disulfide or in a mixed disulfide arising from the reaction of rhodanese with the original disulfide. Extending the reaction time and addition of chloride anion (a nucleophile) did not significantly change the results of the experiment. Using ultrasound as a means of accelerating bond cleavage also had a minimal effect. Those results ruled out cleavage of the carbon-sulfur bond in the original disulfide but did not preclude formation of a mixed disulfide. S-Methyl methylthiosulfonate (MTSO) was used to determine whether a mixed disulfide, if formed, would result in transfer of a sulfur atom to rhodanese. While no thiocyanate was formed in the reaction between cyanide and rhodanese exposed to MTSO, NMR analysis revealed that MTSO reacted directly with cyanide anion to form methyl thiocyanate. This result reveals the body's possible use of oxidized disulfides as a first line of defense against cyanide intoxication. The oxidation of disulfides to the corresponding thiosulfinate or thiosulfonate will result in facilitating their reaction with other nucleophiles. The reaction of an oxidized disulfide with a sulfur nucleophile from glutathione could be a plausible origin for the cyanide metabolite 2-aminothiazoline-4-carboxylic acid.

Organ-distribution of the metabolite 2-aminothiazoline-4-carboxylic acid in a rat model following cyanide exposure

“…The formation mechanism of stable cyanide-protein adducts, such as the reaction of cyanide with the C-terminal Cys 558 Cys 567 disulfide bond of human serum albumin (Fasco et al 2011), is similar to that of ATCA. It has been suggested in an in vivo study that the reaction of an oxidized disulfide with a sulfur nucleophile from glutathione could be a plausible origin for ATCA (Zottola et al 2009). It is likely that endogenous levels of ATCA in each organ reflect the availability of disulfide and the concentration of glutathione in those organs.…”

Cyanide and the human brain: perspectives from a model of food (cassava) poisoning

“…Most insight on the site of the lesion in konzo has been provided by electrophysiological studies, which suggest that both motor and somatosensory pathways, as well as visual pathways, are affected (Table ) . Additional insights have been gained from experimental studies, which suggest that the neuropathology of konzo may be mediated through mechanisms of oxidative damage or protein carbamoylation induced by cyanide (prooxidant) or cyanate (cyanide metabolite, motor system toxicant, and protein‐carbamoylating agent) . We recently confirmed the association between the serum levels of 8,12‐ iso ‐iPF2α‐VI F2‐isoprostane isomer, a marker of lipid peroxidation and thus oxidative damage, and the extent of neurocognitive deficits found in children with konzo (Fig.…”

Synthesis of Symmetrical and Unsymmetrical Thiosulfonates from Disulfides through Electrochemically Induced Disulfide Bond Metathesis and Site‐Selective Oxidation

“…One representative of this substance class are thiosulfonates that act antimicrobial, antifungal, and antiviral [1–4] . In addition, they might be applied in cancer treatment or as antidote in case of cyanide poisoning [5–8] . In the synthetic, organic chemistry these compounds are used as popular sulfenylating agents [9–14] .…”