Modeling Cholinesterase Inhibition

Details

• Personal Author:
  Hinderliter PM ; Poet TS ; Timchalk C
• Description:
  This chapter is focused on the development and application of pharmacokinetic (PK) and pharmacodynamic (PD) models to better understand the toxicology of organophosphosphorus (OP) and carbamate insecticides and chemical warfare agents (CWA) in animals and humans. Although both PK and PD elements of the model will be described, the primary focus will be on highlighting the PD components within the model structure. In this regard, the approach will not entail a comprehensive review of the extensive literature, but rather a focused presentation highlighting important principles using more recently published models for organophosphorus insecticides as specific examples. Organophophorus and carbamate insecticides and chemical warfare agents have high affinity for binding to and inhibiting the enzyme acetylcholinesterase (AChE), and enzyme specifically responsible for the destruction of the neurotransmitter acetylcholine (Ach) within nerve tissue (Wilson, 2001; Ecobichon, 2001). Since the cholinergic system is widely distributed within both the central and peripheral nervous systems, chemicals that inhibit AChE are known to produce a broad range of well characterized symptoms (for a review see Savolainen, 2001). A comparison of the AChE inhibition dynamics for the interaction of ACh, carbaryl (carbamate), chlorpyrifos-oxon (organophophate), and Sarin with AChE is illustrated in Figure 6.1. All four substrates have relatively high affinities for AChE and will readily complex with the enzyme. However, the rates of hydrolysis and reactivation of AChE following carbamylation or phosphorylation of the active site will be drastically slower than for the hydrolysis of the acetylated enzyme (Ecobichon, 2001). Specifically, the turnover time for the neurotransmitter ACH is on the order of more or less 150 microsec; whereas, the carbamylated enzyme t1/2 for hydrolysis is substantially slower (more or less 15-30 min). the phosphorylated enzyme is highly stable (t1/2 more or less days) and further dealkylation of the phosphorylation group produces and "aged" AChE enzyme which is irreversibly inhibited (Taylor, 1980; Murphy, 1986; Ecobichon, 2001; Sogorb and Vilanova, 2002). [Description provided by NIOSH]
• Subjects:
  Animals Carbamates Enzymes Insecticides Occupational Health Safety Toxicology
• Keywords:
  Chemical Warfare Agents Cholinergic Receptors Cholinesterase Inhibitors Humans Hydrolysis Models Nerve Tissue Neurotransmitters Organophosphorus Compounds Organophosphorus Insecticides Pharmacodynamics

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• ISBN:
  9780470998090
• Publisher:
  John Wiley and Sons, Ltd.
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Book
• Place as Subject:
  OSHA Region 10 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  137-165
• NIOSHTIC Number:
  nn:20050581
• Citation:
  Quantitative modeling in toxicology. Krishnan K, Andersen ME, eds. West Sussex, United Kingdom: John Wiley & Sons Ltd., 2010 May; :137-165
• CAS Registry Number:
  Carbaryl (CAS RN 63-25-2) ; Sarin (CAS RN 107-44-8)
• Editor(s):
  Krishnan K; Andersen ME
• Federal Fiscal Year:
  2010
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  Battelle Memorial Institute, Richland, Washington
• Peer Reviewed:
  False
• Start Date:
  20010930
• Source Full Name:
  Quantitative modeling in toxicology
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a8af0ac533a9fb4bf5b403080c3961470ad045293b3fd5bb966ded40702e0171fbca0dc79b116168ab9182ce920dacfee34a66bb0e8edc8f8740ab50636425e0
• Download URL:
  https://stacks.cdc.gov/view/cdc/210870/cdc_210870_DS1.pdf
• File Type:
  [PDF - 1.05 MB ]