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Comparative effectiveness of organophosphorus protoxicant activating systems in neuroblastoma cells and brain
Abstract:
The ability of bromine and rat liver microsomes (RLM) to convert organophosphorus (OP) protoxicants to esterase inhibitors was determined by measuring acetylcholinesterase (AChE) and neuropathy target esterase (NTE) inhibition. Species specific differences in susceptibility to esterase inhibition were determined by comparing the extent of esterase inhibition observed in human neuroblastoma cells and hen, bovine, and rodent brain homogenates. OP protoxicants examined included tri-o-tolyl phosphate (TOTP), O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN), leptophos, fenitrothion, fenthion, and malathion. Bromine activation resulted in greater AChE inhibition than that produced by RLM activation for equivalent concentrations of fenitrothion, malathion, and EPN. For EPN and leptophos, bromine activation resulted in greater inhibition of NTE than RLM. Only preincubation with RLM activated TOTP; resultant inhibition of AChE was less in hen brain (13 +/- 3%) than in neuroblastoma cells (73 +/- 1%) at 10(-6) M. In contrast, 10(-6) M RLM-activated TOTP produced more inhibition of hen brain NTE (89 +/- 6%) than NTE of human neuroblastoma cells (72 +/- 7%). Human neuroblastoma cells and brain homogenates from hens, the accepted animal model for study of OP-induced neurotoxicity, were relatively similar in sensitivity to esterase inhibition. Homogenates from hens were more sensitive to NTE inhibition induced by phenyl saligenin phosphate (PSP), an active congener of TOTP, than were homogenates from less susceptible species (mouse, rat, bovine). AChE of hen brain homogenates was also more sensitive than homogenates from other species to malaoxon, the active form of malathion.
Insights
Bromine and rat liver microsomes (RLM) activate organophosphorus (OP) compounds into esterase inhibitors. Hens and human neuroblastoma cells showed similar sensitivity to OP-induced esterase inhibition, with hens being more susceptible to neurotoxic effects.
Area of Science:
- Biochemistry
- Toxicology
- Neuroscience
Background:
- Organophosphorus (OP) compounds are prevalent environmental and industrial chemicals.
- Many OP compounds are protoxicants, requiring metabolic activation to exert their toxic effects.
- Understanding the metabolic activation pathways and species-specific susceptibility is crucial for risk assessment.
Purpose of the Study:
- To compare the ability of bromine and rat liver microsomes (RLM) to activate OP protoxicants into acetylcholinesterase (AChE) and neuropathy target esterase (NTE) inhibitors.
- To investigate species-specific differences in susceptibility to OP-induced esterase inhibition using human neuroblastoma cells and various animal brain homogenates.
Main Methods:
- Organophosphorus protoxicants (e.g., TOTP, EPN, leptophos, fenitrothion, fenthion, malathion) were incubated with bromine or RLM.
- AChE and NTE inhibition were measured to assess esterase inhibition.
- Esterase inhibition was compared across human neuroblastoma cells, hen, bovine, and rodent brain homogenates.
Main Results:
- Bromine activation yielded greater AChE inhibition than RLM for fenitrothion, malathion, and EPN.
- Bromine activation resulted in higher NTE inhibition than RLM for EPN and leptophos.
- Hen brain homogenates and human neuroblastoma cells exhibited similar sensitivity to OP-induced esterase inhibition, with hens showing higher susceptibility to NTE inhibition by specific OP congeners.
Conclusions:
- Both bromine and RLM can activate OP protoxicants, with differential efficacy depending on the specific OP compound.
- Hens serve as a relevant model for studying OP-induced neurotoxicity due to their sensitivity to esterase inhibition, comparable to human neuroblastoma cells.
- Species-specific differences in esterase inhibition highlight the importance of considering various species in toxicological assessments of OP compounds.
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