Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs

Abstract

Valiyaveettil, Manojkumar; Alamneh, Yonas; Rezk, Peter; Perkins, Michael W.; Sciuto, Alfred M.; Doctor, Bhupendra P.; and Nambiar, Madhusoodana P., "Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs" (2011 b s t r a c tTo explore the efficacy of paraoxonase 1 (PON1) as a catalytic bioscavenger, we evaluated human recombinant PON1 (rePON1) expressed in Trichoplusia ni larvae against sarin and soman toxicity using microinstillation inhalation exposure in guinea pigs. Animals were pretreated intravenously with catalytically active rePON1, followed by exposure to 1.2 X LCt 50 sarin or soman. Administration of 5 units of rePON1 showed mild increase in the blood activity of the enzyme after 30 min, but protected the animals with a significant increase in survival rate along with minimal signs of nerve agent toxicity. Recombinant PON1 pretreated animals exposed to sarin or soman prevented the reduction of blood O 2 saturation and pulse rate observed after nerve agent exposure. In addition, rePON1 pretreated animals showed significantly higher blood PON1, acetylcholinesterase (AChE), and butyrylcholinesterase activity after nerve agent exposure compared to the respective controls without treatments. AChE activity in different brain regions of rePON1 pretreated animals exposed to sarin or soman were also significantly higher than respective controls. The remaining activity of blood PON1, cholinesterases and brain AChE in PON1 pretreated animals after nerve agent exposure correlated with the survival rate. In summary, these data suggest that human rePON1 protects against sarin and soman exposure in guinea pigs.

Catalytic bioscavengers in nerve agent poisoning: A promising approach?

“…60% of parathion poisoned rats while all methyl-parathion exposed rats survived 16 h but none 24 h. Prophylactic administration of encapsulated wild-type PTE protected mice from multiple LD 50 s of paraoxon and diisopropylfluorophosphate (Wales and Reeves, 2012). Recombinant wild-type PON1 given 30 min prior to 1.2LCT 50 sarin or soman resulted in a significantly higher survival rate compared to agent control guinea pigs (Valiyaveettil et al, 2011) while Trichoplusia ni larvae expressed rePON1 failed to protect guinea pigs from 2LD 50 tabun, sarin soman or cyclosarin .…”

“…Enzymes with a preference for P-O bond cleavage are referred to as OP hydrolases (e.g., paraoxonase and bacterial phosphotriesterase, EC 3.1.8.1) and those with a preference for P-F or P-CN bonds are termed diisopropylfluorophosphatases (e.g., DFPase; EC 3.1.8.2) In the meantime, research focused on human paraoxonase (PON1) and bacterial PTE as potential catalytic bioscavengers (Masson and Rochu, 2009), although other enzymes, e.g., prolidase, laccase and other bacterial enzymes, are under investigation as well (Amitai et al, 1998;Rezk et al, 2015;Otto et al, 2013). In fact, the prophylactic administration of OP hydrolases in different animal species provided protection against various OP compounds in different species (Ashani et al, 1991;Bird et al, 2008;Gresham et al, 2010;Valiyaveettil et al, 2011;Worek et al, 2014a;Raveh et al, 1992).…”

Epidemiologic Evidence of Health Effects from Long-Distance Transit of Chemical Weapons Fallout from Bombing Early in the 1991 Persian Gulf War

“…The PON1 gene and the serum activity of its polymorphic Q and R isoenzyme products are the main determinants of the level of an individual's resistance to the brain effects of organophosphate pesticides and nerve agents, including sarin [28,29,30]. The level of serum activity of the Q isoenzyme, the main determinant of susceptibility to sarin, varies widely in the population, and was found in a small study to be associated with Gulf War illness [31,32].…”

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

“…Although BChE is the most widely suggested bioscavenger for OP toxicity, hPON-1 has been advocated as a possible alternative with better results. Recently, Valiyaveettil et al (2011) used recombinant PON-1 (rePON-1) expressed in Trichoplusia (cabbage looper) in larvae against sarin and soman toxicity using micro instillation inhalation exposure in guinea pigs. PON1, a catalytic scavenger, hydrolyzes many OPs including paraxoxon, diazoxon, and chlorpyrifos oxon as well as the nerve agents sarin, soman, VX, and VR.…”