Upstream eventInhibition, Acetylcholinesterase (AchE)
Accumulation, Acetylcholine in synapses
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||adjacent||High||Moderate|
|Acetylcholinesterase Inhibition Leading to Neurodegeneration||adjacent||High||Moderate|
Life Stage Applicability
Key Event Relationship Description
- AChE is an enzyme responsible for controlling the level of acetylcholine available at neuromuscular junctions by degradation via hydrolysis to acetic acid and choline (Wilson 2010). Inhibition of AChE prevents degradation of acetylcholine which leads to accumulation of acetylcholine in synapses associated with muscarinic and nicotinic receptors (Soreq and Seidman, 2001; Lushington 2006).
- See KEGG Reaction R01026
Evidence Supporting this KER
- Given the role of AChE in catalyzing degradation of acetylcholine into choline and acetate, it is highly plausible that inhibition of this enzyme activity would lead to acetylcholine accumulation.
Include consideration of temporal concordance here
- The literature includes many studies linking increases in acetylcholine in brain tissues after exposure to an OP or carbamate pesticide with increased AChE inhibition in various taxa. Examples include studies with crustacea (Reddy et al., 1990); tadpoles (Nayeemunnisa and Yasmeen, 1986); fish (Rao and Rao 1984; Verma et al., 1981); birds (Kobayashi et al., 1983); and rodents (Kobayashi et al., 1988).
- In a study where female ICR mice were exposed to either the fenobucarb or propoxur, authors reported a significant increase in acetylcholine in brain tissue 10 minutes after injection, with a concurrent significant increase in AChE inhibition (Kobayashi et al., 1985).
- An acute (48h) sublethal exposure to methyl parathion found that AChE levels in brain tissue in fish (Oreochromis mossambicus) were significantly inhibited at all measured durations ranging from 12-48 hrs with inhibition increasing from 36-62% as compared to controls over the time span (Rao and Rao, 1984). The researchers found a significant increase in acetylcholine at all time courses measured (12-48hr) with acetylcholine levels increasing from 33-83% as compared to controls over the same time span (Rao and Rao, 1984).
- A study of quail (Coturnix japonica) exposed to lethal concentrations of two OP pesticides (i.e., DDVP or fenitrothion), found significant increases in total and free acetylcholine, and significant inhibition of AChE as compared to controls (Kobayashi et al., 1983).
- Measurements (in vitro) of AChE inhibition, acetylcholine and electrophysiological responses on the pedal ganglion of the gastropod Aplysia californica, were found to be dose-dependent, with increase in dose resulting in increased AChE inhibition, increased levels of acetylcholine, and a decrease in the electrophysiological response (Oyama et al., 1989).
- Wister rats injected with a sublethal concentration of dichlorvos found a significant decrease in AChE activity, increased acetylcholine concentrations, and enhanced contractile responses in jejunum muscle (Kobayashi et al., 1994).
- At sublethal concentrations ( 56% of the LD50), researchers found a statistically significant (18%) increase in the amount of acetylcholine in brain tissue of Charles River rats exposed to disulfoton for 3 days, with measured AChE inhibition of 68% as compared to controls (Stavinoha et al., 1969).
- An acute sublethal exposure of chlorpyrifos to Sprague-Dawley rats found significant dose and time related effects including increased inhibition of AChE, increased levels of acetylcholine, and significant impacts to motor activity (nocturnal rearing response) (Karanth et al., 2006).
Uncertainties and Inconsistencies
- No known qualitative inconsistencies or uncertainties associated with this relationship.
Quantitative Understanding of the Linkage
The general kinetic equation is: AChE + AX □(⇔┴k1 ) AChE-AX □(→┴k2 ) AChE-A + X □(→┴k3 ) AChE + A Where AX is the substrate, either acetylcholine or an inhibitor of AChE (e.g., OP or carbamate); AChE-AX is the enzyme-substrate complex; AChE-A is the acylated, carbamylated or phosphorylated enzyme; X is the leaving group (e.g., choline); AChE is the free enzyme; and A is acetic acid, phosphate (P(=O)(=O)(R2)or methylamine. In a normally functioning enzyme system k1 is the rate-limiting step for hydrolysis of acetylcholine, but k3 is the rate limiting step when AChE is inhibited by carbamates or OPs (Wilson 2010).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Wilson, B.W. 2010. Cholinesterases. IN: Kreiger, R. (Ed.). Hayes’ Handbook of Pesticide Toxicology. Third Edition, Volume 2. Elsevier, Amsterdam, The Netherlands. pp. 1457-1478.
- Soreq, H. and S. Seidman. 2001. Acetylcholinesterase – new roles for an old actor. Nat. Rev. Neurosci. 2: 294-302.
- Lushington, G.H., J-X. Guo, and M.M. Hurley. 2006. Acetylcholinesterase: Molecular modeling with the whole toolkit. Curr. Topics Medic. Chem. 6: 57-73.
- Reddy, M. S., Jayaprada, P., and Rao, K. V. R. 1990. Impact of Methylparathion and Malathion on Cholinergic and Non-Cholinergic Enzyme Systems of Penaeid Prawn, Metapenaeus monoceros. Biochem.Int. 22, 769-780.
- Nayeemunnisa and Yasmeen, N. 1986. On the Presence of Calmodulin in the Brain of Control and Methyl Parathion-Exposed Developing Tadpoles of Frog, Rana cyanophlictis. Curr.Sci.(Bangalore) 55, 546-548.
- Rao, K. S. P. and Rao, K. V. R. 1984. Impact of Methyl Parathion Toxicity and Eserine Inhibition on Acetylcholinesterase Activity in Tissues of the Teleost (Tilapia mossambica) - a Correlative Study. Toxicol.Lett. 22, 351-356.
- Verma, S. R., Tonk, I. P., Gupta, A. K., and Dalela, R. C. 1981. In Vivo Enzymatic Alterations in Certain Tissues of Saccobranchus fossilis Following Exposure to Four Toxic Substances. Environ.Pollut.A. 26, 121-127.
- Kobayashi, H., Yuyama, A., Ohkawa, T., and Kajita, T. 1988. Effect of Single or Chronic Injection with a Carbamate, Propoxur, on the Brain Cholinergic System and Behavior of Mice. Jpn.J.Pharmacol. 47, 21-27.
- Kobayashi, H., Yuyama, A., Kudo, M., and Matsusaka, N. 1983. Effects of Organophosphorus Compounds, O,O-Dimethyl O-(2,2-Dichlorovinyl)Phosphate (DDVP) and O,O-Dimethyl O-(3-Methyl 4-Nitrophenyl)Phosphorothioate (Fenitrothion), on Brain Acetylcholine Content and Acetylcholinesterase Activity in Japanese Quail. Toxicology 28, 219-227.
- Kobayashi,H., A. Yuyama, T. Kajita, K. Shimura, T. Ohkawa, and K. Satoh. 1985. Effects of Insecticidal Carbamates on Brain Acetylcholine Content, Acetylcholinesterase Activity and Behavior in Mice. Toxicol. Lett.29(2-3): 153-159.
- Oyama, Y., N. Hori, M.L. Evans, C.N. Allen, and D.O. Carpenter. 1989. Electrophysiological estimation of the actions of acetylcholinesterase inhibitors on acetylcholine receptor and cholinesterase in physically isolated Aplysia neurons. Br. J. Pharmacol. 96:573-582.
- Kobayashi, H., Sato, I., Akatsu, Y., Fujii, S. I., Suzuki, T., Matsusaka, N., and Yuyama, A. 1994. Effects of Single or Repeated Administration of a Carbamate, Propoxur, and an Organophosphate, DDVP, on Jejunal Cholinergic Activities and Contractile Responses in Rats. J.Appl.Toxicol. 14, 185-190.
- Stavinoha, W. B., Ryan, L. C., and Smith, P. W. 1969. Biochemical Effects of an Organophosphorus Cholinesterase Inhibitor on the Rat Brain. Ann.N.Y.Acad.Sci. 160, 378-382.
- Karanth, S., Liu, J., Mirajkar, N., and Pope, C. 2006. Effects of Acute Chlorpyrifos Exposure on In Vivo Acetylcholine Accumulation in Rat Striatum. Toxicol.Appl.Pharmacol. 216, 150-156.