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Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat.
Toxicol Appl Pharmacol. 1996 Jan; 136(1):20-8.TA

Abstract

These experiments examined the changes in acetylcholinesterase (AChE) during tolerance development in rats exposed to paraoxon, an irreversible inhibitor of AChE. Rats were injected sc for 20 days with 0.09, 0.12, or 0.19 mg/kg of paraoxon. Tolerance to the clinical signs of paraoxon toxicity developed rapidly. The hypothesis was tested that changes in the kinetics of reactivity of AChE with its substrate acetylcholine (ACh) and the inhibitor paraoxon contribute to the observed tolerance. The kinetic constants Vmax and Km were determined by Lineweaver-Burk transformations. The affinity (Kd), phosphorylation (kp) and the bimolecular rate (ki) constants were established from slopes and standard deviations of inhibition curves. Acetylcholinesterase properties of brain and diaphragm from controls and paraoxon-tolerant rats were compared. In controls, Km, determining the affinity of AChE for ACh, was 0.063 x 10(-3) M and 0.072 x 10(-3) M for diaphragm and brain, respectively. In paraoxon-tolerant rats, the affinity of AChE for ACh increased since the Km for diaphragm was reduced to 0.047 x 10(-3) M and the Km for brain to 0.057 x 10(-3) M. This decrease was seen with all paraoxon concentrations and was significantly different from controls after the fifth day of treatment. Small, significant increases of IC50 values for paraoxon were observed in diaphragm (from 27.30 to 45.14 nM) and in brain (from 13.67 to 15.38 nM). In brain, a 20-day treatment with paraoxon caused a fivefold decrease in the dissociation constant (Kd) from 1.56 to 0.268 microM and a threefold decrease in the phosphorylation constant (kp) from 4.72 to 1.52 min-1. The observed changes in diaphragm were smaller and not significant. The increase in affinity to ACh gives an advantage to tolerant rats, because the remaining reduced amount of AChE can hydrolyze ACh more efficiently, regardless of the change in sensitivity to the inhibitor. The observed changes may be the result of structural changes of AChE or the result of altered levels of preexisting isozymes of AChE.

Authors+Show Affiliations

Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tennessee 37212, USA.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8560475

Citation

Milatovic, D, and W D. Dettbarn. "Modification of Acetylcholinesterase During Adaptation to Chronic, Subacute Paraoxon Application in Rat." Toxicology and Applied Pharmacology, vol. 136, no. 1, 1996, pp. 20-8.
Milatovic D, Dettbarn WD. Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat. Toxicol Appl Pharmacol. 1996;136(1):20-8.
Milatovic, D., & Dettbarn, W. D. (1996). Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat. Toxicology and Applied Pharmacology, 136(1), 20-8.
Milatovic D, Dettbarn WD. Modification of Acetylcholinesterase During Adaptation to Chronic, Subacute Paraoxon Application in Rat. Toxicol Appl Pharmacol. 1996;136(1):20-8. PubMed PMID: 8560475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat. AU - Milatovic,D, AU - Dettbarn,W D, PY - 1996/1/1/pubmed PY - 1996/1/1/medline PY - 1996/1/1/entrez SP - 20 EP - 8 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 136 IS - 1 N2 - These experiments examined the changes in acetylcholinesterase (AChE) during tolerance development in rats exposed to paraoxon, an irreversible inhibitor of AChE. Rats were injected sc for 20 days with 0.09, 0.12, or 0.19 mg/kg of paraoxon. Tolerance to the clinical signs of paraoxon toxicity developed rapidly. The hypothesis was tested that changes in the kinetics of reactivity of AChE with its substrate acetylcholine (ACh) and the inhibitor paraoxon contribute to the observed tolerance. The kinetic constants Vmax and Km were determined by Lineweaver-Burk transformations. The affinity (Kd), phosphorylation (kp) and the bimolecular rate (ki) constants were established from slopes and standard deviations of inhibition curves. Acetylcholinesterase properties of brain and diaphragm from controls and paraoxon-tolerant rats were compared. In controls, Km, determining the affinity of AChE for ACh, was 0.063 x 10(-3) M and 0.072 x 10(-3) M for diaphragm and brain, respectively. In paraoxon-tolerant rats, the affinity of AChE for ACh increased since the Km for diaphragm was reduced to 0.047 x 10(-3) M and the Km for brain to 0.057 x 10(-3) M. This decrease was seen with all paraoxon concentrations and was significantly different from controls after the fifth day of treatment. Small, significant increases of IC50 values for paraoxon were observed in diaphragm (from 27.30 to 45.14 nM) and in brain (from 13.67 to 15.38 nM). In brain, a 20-day treatment with paraoxon caused a fivefold decrease in the dissociation constant (Kd) from 1.56 to 0.268 microM and a threefold decrease in the phosphorylation constant (kp) from 4.72 to 1.52 min-1. The observed changes in diaphragm were smaller and not significant. The increase in affinity to ACh gives an advantage to tolerant rats, because the remaining reduced amount of AChE can hydrolyze ACh more efficiently, regardless of the change in sensitivity to the inhibitor. The observed changes may be the result of structural changes of AChE or the result of altered levels of preexisting isozymes of AChE. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/8560475/Modification_of_acetylcholinesterase_during_adaptation_to_chronic_subacute_paraoxon_application_in_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(96)90003-4 DB - PRIME DP - Unbound Medicine ER -