title: Interactions of neuropathy inducers and potentiators/promoters with soluble esterases.
abstract: Organophosphorus compounds (OPs) cause neurotoxic disorders through interactions with well-known target esterases, such as acetylcholinesterase and neuropathy target esterase (NTE). However, the OPs can potentially interact with other esterases of unknown significance. Therefore, identifying, characterizing and elucidating the nature and functional significance of the OP-sensitive pool of esterases in the central and peripheral nervous systems need to be investigated. Kinetic models have been developed and applied by considering multi-enzymatic systems, inhibition, spontaneous reactivation, the chemical hydrolysis of the inhibitor and "ongoing inhibition" (inhibition during the substrate reaction time). These models have been applied to discriminate enzymatic components among the esterases in nerve tissues of adult chicken, this being the experimental model for delayed neuropathy and to identify different modes of interactions between OPs and soluble brain esterases. The covalent interaction with the substrate catalytic site has been demonstrated by time-progressive inhibition during ongoing inhibition. The interaction of sequential exposure to an esterase inhibitor has been tested in brain soluble fraction where exposure to one inhibitor at a non inhibitory concentration has been seen to modify sensitivity to further exposure to others. The effect has been suggested to be caused by interaction with sites other than the inhibition site at the substrate catalytic site. This kind of interaction among esterase inhibitors should be considered to study the potentiation/promotion phenomenon, which is observed when some esterase inhibitors enhance the severity of the OP induced neuropathy if they are dosed after a non neuropathic low dose of a neuropathy inducer.
authors.affiliation: University Miguel Hernandez of Elche, Institute of Bioengineering, Unit of Toxicology and Chemical Safety, Alicante, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Estévez
authors.forename: Iris
authors.initials: I
authors.lastname: Mangas
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Sogorb
authors.forename: Eugenio
authors.initials: E
authors.lastname: Vilanova
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D020134:Catalytic Domain; D002645:Chickens; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004950:Esterases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007531:Isoflurophate / Q000031:analogs & derivatives / Q000633:toxicity; D007700:Kinetics; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010261:Paraoxon / Q000633:toxicity; D010664:Phenylmethylsulfonyl Fluoride / Q000633:toxicity; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D007531:Isoflurophate; C005238:mipafox; D010664:Phenylmethylsulfonyl Fluoride; D004950:Esterases; D010261:Paraoxon