Cyanide and Cyanogenic Compounds-Toxicity, Molecular Targets, and Therapeutic Agents

Abstract

Cyanide (CN) is a well-known mitochondrial poison. CN poisoning may result from acute or long-term exposure to a number of CN compounds. Recent insight into the chemical affinities of the CN anion has increased our understanding of its toxicity and the mechanisms of antidotal actions, which, together with information on various exposure sources, are reviewed in the present article. A literature search in Scopus, Embase, Web of Science, PubMed, and Google Scholar for the period 2001-2024 revealed that the CN anion after exposure or degradation of CN compounds is distributed to vulnerable copper and iron-containing targets, especially in mitochondria, thus blocking the electron transport chain. Intake of cyanogenic compounds may exert subacute or chronic toxic effects, also because of the interaction with cobalt in vitamin B₁₂. Antidotal agents exert their effects through the affinity of CN for cobalt- or iron-containing compounds. Research on CN interactions with metalloproteins may increase our insight into CN toxicity and efficient antidotal regimens.

Keywords: cobalamin; cyanide; cyanogenic compounds; iron(III); methaemoglobin; mitochondria; poisoning.

Figure 1

Routes of cyanide (CN) exposure or its precursors/derivatives may occur via inhalation and skin contact with combustion smoke (fabrics or biological samples containing nitrogen and carbon atoms) or via ingestion (accidental or during murder/suicide attempts) of contaminated water and cyanogenic food. The acute lethal oral dose of cyanide in humans is reported to be between 0.5 and 3.5 mg/kg bodyweight (BW). The toxic threshold value for cyanide in blood is considered to be between 0.5 mg/L (ca.20 µM) and 1.0 mg/L (ca. 40 µM); the lethal threshold value ranges between 2.5 mg/L (ca. 100 µM) and 3.0 mg/L (ca. 120 µM).

Figure 2

Release of cyanide from cyanogenic glycosides (CNGs) and biotransformation of cyanide. R¹ = phenyl/p-hydroxyphenyl/methyl and R² = hydrogen/methyl/ethyl, substituents, sugar = glucose (S or R)/gentobiose (R). Release of cyanide: (A); detoxification: (B), cyanoalanine, (C) 2-amino-2-thiozoline4-caroxcylic acid (ATCA), (D), thiocyanate and (E) α-ketoglutarate cyanohydrin (α-KgCN).

Figure 3

Regarding the consecutive complexes I–IV in the electron transport chain, cyanide poisoning results in an arrest in the electron flow to complex IV (which depends upon heme as a cofactor). CN⁻ has a high affinity for the ferric iron (heme a3) on cytochrome c oxidase, forming an adduct, which formation leads to inhibition of the electron transport chain.