engleski

Introductory overview on mechanisms of organophosphate toxicity and detoxication with emphasis on studies in Croatia

Organophosphates (OP) are highly toxic compounds that are used as pesticides, drugs, and also as warfare nerve agents. Cholinesterases (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE) and phosphoric triester hydrolases (paraoxonase, PON, and DFPase) are involved in toxicity and detoxication of these agents. AChE and BChE are inhibited by Ops, while PON and DFPase hydrolyse OPs. The molecular structure of these enzymes and their mechanisms of interaction with OPs have by-and-large been resolved and generally understood. Present studies are mainly directed towards details concerning enzyme structure, role of individual residues in the enzyme interaction with OPs, search for effective antidotes decontaminating agents against OPs, and developing methods to identify OPs in humans and in the environment. Studies in Croatian laboratories have comprised several approaches relevant for the toxicity of OPs. Due to individual differences in the susceptibility to OPs, and to some other pharmacologically active compounds, the catalytic properties and distribution profiles of BChE and PON variants were analyzed in healthy population groups in Croatia. Activities and distribution profiles of variants were also analyzed in relation to certain diseases. Over several decades, about 150 compounds were synthesized and tested (on rodents) as antidotes, particularly against Sarin, Soman, Tabun and VX. These compounds contained pyridinium, imidasolium or quinuclidinium moieties with one or two oxime groups, and some achieved satisfactory therapeutic effect as compared to the conventional antidotes. The kinetics of in vitro reactivation of phosphylated cholinesterases and the protection of the enzyme against inhibition by OPs was studied. Reaction models concerning binding of reversible ligands (including oximes) to the catalytic and/or allosteric enzyme sites were proposed and tested. Several methods for measuring cholinesterase activities in human blood were validated and recommended as field methods for assessing OP absorption. Quality control studies for measurement of BChE activities and for identifying BChE variants were conducted, and introduced in several clinical laboratories in Croatia.

organophosphate toxicity; detoxication; overview; Croatia

http://dx.doi.org/10.1016/j.toxlet.2006.06.022 ; DOI: 10.1016/j.toxlet.2006.06.02