Differential toxicity of abrin in human cell lines of different organ origin.

Abrus precatorius is a highly toxic seed containing the poison abrin. Similar in properties to ricin, this toxin binds to ribosomes causing cessation of protein synthesis and cell death. With an estimated human lethal dose of 0.1-1 µg/kg, it has been the cause of fatalities due to accidental and intentional ingestion. In present study, we profiled seven human cell lines of different organ origin, for their sensitivity against abrin toxicity. These cell lines are, A549, COLO 205, HEK 293, HeLa, Hep G2, Jurkat, SH-SY5Y and derived from lung, intestine, kidney, cervix, liver, immune and nervous system respectively. MTT, NR, CVDE and LDH assays have been used to determine their response against abrin toxin. Among these cell lines A549 was the most sensitive cell line while Hep G2 was found least sensitive cell lines. Hep G2 cells are shown to have mitochondrial resistance and delayed generation of oxidative stress compared to A549 cells. Remarkable variation in sensitivity against abrin toxicity prompted the evaluation of Bcl2, Bax and downstream caspases in both cells. Difference in Bcl2 level has been shown to play important role in variable sensitivity. Findings of present study are helpful for selection of suitable cellular model for toxicity assessment and antidote screening.

E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide targets abrin and ricin toxicity: Hitting two toxins with one stone.

The efficacy of small molecule inhibitors (SMIs) against the enzymatic activity of Shiga toxin prompted the evaluation of their efficacy on related toxins viz. ricin and abrin. Ricin, like Shiga toxin, is listed as a category B bioweapon and belongs to the type II family of ribosome inactivating proteins (RIPs). Abrin though structurally and functionally similar to ricin, is considerably more toxic. In the present study, 35 compounds were evaluated in A549 cells in in vitro assays, of which 5 offered protection against abrin and 2 against ricin, with IC50 values ranging between 30.5-1379 µM and 300-341 µM, respectively. These findings are substantiated by fluorescence based thermal shift assay. Moreover, the binding of the promising compounds to the toxin components has been validated by Surface Plasmon Resonance assay and in vitro protein synthesis assay. In vivo studies reveal complete protection of mice with compound 4 E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide against orally administered lethal doses of, both, abrin and ricin. The present study thus proposes the emergence of E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide as a lead compound against RIPs.

Dose dependent acute toxicity of abrin in Balb/c mice after intraperitoneal administration.

Abrin toxin is one of the most potent and deadly plant toxin obtained from the seeds of Abrus precatorious. It is more toxic than ricin which is classified as Schedule 1 agent by OPCW and Category B bioterrorism agent by Centre for Disease Control (CDC). Dose dependent acute toxicity of abrin is still a matter of investigation. The present study was carried out to assess the toxicity of abrin from sub lethal to supralethal doses (0.5X, 1X, 2X and 5XLD50) after intraperitoneal administration. After 8 and 24h of abrin exposure, hematological, biochemical, inflammatory and oxidative stress associated parameters were analyzed. Liver histology was also done to analyze the effect of abrin. Abrin exerts its toxicity in a dose and time dependent manner. Increases in neutrophil counts, lipid peroxidation with decreased lymphocyte counts, are the initiating factor irrespective of time and dose. At higher doses of abrin there was a decrease in hemoglobin level and RBC count which is reflected by increased levels of serum ammonia and bilirubin. Neutrophil infiltration in the liver and lipid peroxidation cause liver toxicity (increased production of ALT and ALP); oxidative stress (depletion of GSH and total antioxidant status); inflammation (increased production of TNF-α and IFN-γ). Further, at higher doses of abrin, intensity of oxidative stress, inflammation and liver toxicity are more pronounced which may have been maintained by the self-sustaining loop of toxicity leading to death of the animals.

Prophylactic efficacy of some chemoprotectants against abrin induced lethality.

Abrin is a highly toxic protein produced by Abrus precatorius. Exposure to abrin, either through accident or by act of terrorism, poses a significant risk to human health and safety. Abrin functions as a ribosome-inactivating protein by depurinating the 28S rRNA and inhibits protein synthesis. It is a potent toxin warfare agent. There are no antidotes available for abrin intoxication. Supportive care is the only option for treatment of abrin exposure. It is becoming increasingly important to develop countermeasures for abrin by developing pre- and post-exposure therapy. The aim of this study is to screen certain pharmaceutical compounds for their chemoprotective properties against abrin toxicity in vivo in BALB/c male mice. Twenty-one compounds having either antioxidant, anti-inflammatory and cyto-protective properties or combination of them, were screened and administered as 1h pre-treatment followed by exposure of lethal dose (2×LD50, intraperitoneally) of abrin. To assess the protective efficacy of the compounds, survival and body weight was monitored. Fifteen compounds extended the survival time of animals significantly, as compared to abrin. The following five of these compounds, namely: Epicatechin-3-gallate, Gallic Acid, Lipoic Acid, GSH and Indomethacin extended the life time ranging from 6 to 9 days. These compounds also attenuated the abrin induced inflammation and enzymes associated with liver function, but none of them could prevent abrin induced lethality. The compounds offering extension of life could be useful to provide a time-window for other supportive treatment and could also be used as combinatorial therapy with other medical countermeasures against abrin induced lethality.