In vitro age-related differences in rats to organophosphates. (April 2021)

• Record Type: Journal Article
• Authors: Meek, Edward C.; Carr, Russell L.; Chambers, Janice E.
• Is Part Of: Toxicology in vitro. Volume 72(2021)
• Publication Date: 2021-04
• Subjects: Organophosphate -- Acetylcholinesterase -- Butyrylcholinesterase -- Carboxylesterase; AChE acetylcholinesterase -- BChE butyrylcholinesterase -- CaE carboxylesterase -- CYP 450 cytochrome P450 -- DTNB 5, 5′-dithio-bis(nitrobenzoic acid) -- OP organophosphate -- PND post natal day -- PON paraoxonase -- pNPV p-nitrophenyl valerate -- SCPP saligenin cyclic phenylphosphonate; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105102
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: The mechanism of toxic action for organophosphates (OPs) is the persistent inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and subsequent hyperstimulation of the nervous system. Organophosphates display a wide range of acute toxicities. Differences in the OP's chemistries results in differences in the compound's metabolism and toxicity. Acute toxicities of OPs appear to be principally dependent on compound specific efficiencies of detoxication, and less dependent upon efficiencies of bioactivation and sensitivity of AChE. Serine esterases, such as carboxylesterase (CaE) and butyrylcholinesterase (BChE), play a prominent role in OP detoxication. Organophosphates can stoichiometrically inhibit these enzymes, removing OPs from circulation thus providing protection for the target enzyme, AChE. This in vitro study investigated age-related sensitivity of AChE, BChE and CaE to twelve structurally different OPs in rat tissues. Sensitivity of esterases to these OPs was assessed by inhibitory concentration 50s (IC50 s). The OPs displayed a wide range of inhibitory potency toward AChE with IC50 s in the low nM-μM range with no differences among ages; however, the CaE IC50 s generally increased with age reflecting greater protection in adults. These results suggest age-related differences in acute toxicities of OPs in mammals are primarily a result of their detoxication capacities. Highlights: Organophosphates display a wide range of potency toward acetylcholinesterase. Organophosphate structure affects potency toward acetylcholinesterase. Age-related differences in detoxication of organophosphate affects acute toxicity. Organophosphate acute toxicity is principally dependent on efficiency of detoxication.