An Approach toward Antidotes for Phosphine

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An Approach Toward Antidotes for Phosphine More human poisonings (both accidental and deliberate) are reported worldwide due to phosphine than any other toxic substance. Aluminum and zinc phosphides are legally available from many commercial outlets in pelleted forms for use as rodenticides in the U.S. When these pellets come into contact with water (liquid/vapor) they release phosphine gas and could easily be deployed as weapons. A key target for phosphine is widely believed to be the electron transport chain of mitochondria, but there appears to be adearth of information concerning its toxic mode of action at the biochemical and cellular levels. We proposeto better identify the molecular target(s) of phosphine to facilitate future development of agents to reverse the acute toxicity. Also, since phosphine is a good ligand species, but a relatively slow acting poison mainly eliminated through exhalation, we suggest that a decorporating approach using metal ion complexes must be appropriate for ameliorating phosphine poisoning. The cobalt-containing water-soluble macrocyclic complexes we have recently shown to be effective antidotes to cyanide [Benz et al (2012) Chem. Res. Tox., 25, 2678-86; Ibid (2016)] and sulfide [Cronican et al (2015) Chem. Res. Tox., 28, 1398-1408] in mice are not antidotal toward phosphine. We hypothesize that compounds containing gold(I) will prove to be good candidate antidotes and be non-toxic at the levels required to be efficacious in treating phosphine intoxication. Aim 1. To demonstrate that while phosphine can indeed act as a mitochondrial poison through inhibition of the electron- transport chain at cytochrome c oxidase in mitochondria, that this is of less toxic consequence in vivo than damage to hemoglobin/erythrocytes. Aim 2. To determine if some easily prepared univalent gold complexes antidotal toward phosphine in mice.