In vitro evaluation of the catalytic activity of paraoxonases and phosphotriesterases predicts the enzyme circulatory levels required for in vivo protection against organophosphate intoxications. (25th November 2016)

• Record Type: Journal Article
• Authors: Ashani, Yacov; Leader, Haim; Aggarwal, Nidhi; Silman, Israel; Worek, Franz; Sussman, Joel L.; Goldsmith, Moshe
• Is Part Of: Chemico-biological interactions. Volume 259:Part B(2016)
• Page Start: 252
• Page End: 256
• Publication Date: 2016-11-25
• Subjects: Catalytic scavengers -- Organophosphates -- Nerve agent protection -- Acetylcholinesterase -- Paraoxonase -- Phosphotriesterase; OP organophosphate -- AChE acetylcholinesterase -- rePON1 recombinant paraoxonase -- PTE phosphotriesterase -- CWNA chemical warfare nerve agent -- GF cyclosarin -- DEFP O, O-diethyl fluorophosphate; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.04.039
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Catalytic scavengers of organophosphates (OPs) are considered very promising antidote candidates for preventing the adverse effects of OP intoxication as stand alone treatments. This study aimed at correlating the in-vivo catalytic efficiency ((kcat /KM )[Enzyme]pl ), established prior to the OP challenge, with the severity of symptoms and survival rates of intoxicated animals. The major objective was to apply a theoretical approach to estimate a lower limit for (kcat /KM )[Enzyme]pl that will be adequate for establishing the desired kcat /KM value and plasma concentration of efficacious catalytic bioscavengers. Published data sets by our group and others, from in vivo protection experiments executed in the absence of any supportive medicine, were analyzed. The kcat /KM values of eight OP hydrolyzing enzymes and their plasma concentrations in four species exposed to OPs via s.c., i.m. and oral gavage, were analyzed. Our results show that regardless of the OP type and the animal species employed, sign-free animals were observed following bioscavenger treatment provided the theoretically estimated time period required to detoxify 96% of the OP (t96% ) in vivo was ≤10 s. This, for example, can be achieved by an enzyme with kcat /KM = 5 × 10 7 M −1 min −1 and a plasma concentration of 0.4 μM ((kcat /KM )[Enzyme]pl = 20 min −1 ). Experiments in which animals were intoxicated by i.v. OP injections did not always conform to this rule, and in some cases resulted in high mortality rates. We suggest that in vivo evaluation of catalytic scavengers should avoid the unrealistic bolus i.v. route of OP exposure. Highlights: A lower boundary was set for kcat /KM ×[plasma concentration] for catalytic enzymes. kcat /KM should be 5 × 10 7 M −1 min −1 to protect without symptoms of intoxication. Sign-free animals were observed provided detoxification reached 96% in less than 10 s. Evaluation of catalytic scavengers should avoid the i.v. route of exposure.