Amelioration of Acute Mercury Toxicity by a Novel, Non-Toxic Lipid Soluble Chelator N,N'bis-(2-mercaptoethyl)isophthalamide: Effect on Animal Survival, Health, Mercury Excretion and Organ Accumulation

Abstract

The toxic effects of mercury are known to be complex with specific enzyme inhibitions and subsequent oxidative stress adding to the damaging effects. There are likely other factors involved, such as the development of impaired metal ion homeostasis and depletion of thiol and selenium based metabolites such as cysteine and selenium. Much of the toxicity of mercury occurs at the intracellular level via binding of Hg(2+) to thiol groups in specific proteins. Therefore, amelioration of mercury toxicity by the use of chelation would likely be enhanced by the use of a chelator that could cross the cell membrane and the blood brain barrier. It would be most favorable if this compound was of low toxicity, had appropriate pharmacokinetics, bound and rendered mercury cation non-toxic and had antioxidant properties. Herein we report on such a chelator, N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI), and, using an animal model, show that it prevented the toxic effects associated with acute exposure induced by injected mercury chloride.

Figures

Figure 1

N,N-bis-(2-mercaptoethyl)isophthalamide (NBMI)

Figure 2

Organ mercury levels after subacute mercury exposure ± NBMI Hg levels in each organ was measured 5 days after HgCl2 injection and/or treatment with NBMI. Animals in the “Unexposed” group were treated with saline only. After elimination of outliers in-group comparisons were made using the Kruskal-Wallis test (nonparametric F-test) or oneway ANOVA (group 2 only) to determine statistical significance of differences in mean Hg levels. Between-group comparisons were made using pairwise comparisons using Mann Whitney rank sums tests and a Bonferroni correction. # Mean Hg levels in these organs were significantly higher in “Hg Only” or “Hg and NBMI” groups than in that organ other groups (p<0.0001). * Mean Hg level in the “Hg only” group was not significantly different from the Hg levels in the “Hg + NBMI” group. It was significantly higher than mean Hg levels in other groups (p<0.001). Mean Hg level in the “Hg + NBMI” group was greater than in the “Unexposed” and “NBMI Only” groups.