Contribution of Carboxylesterase and Cytochrome P450 to the Bioactivation and Detoxification of Isocarbophos and Its Enantiomers in Human Liver Microsomes

Toxicol Sci. 2014 Jul;140(1):40-8. doi: 10.1093/toxsci/kfu067. Epub 2014 Apr 20.


Organophosphorus pesticides are the most widely used pesticides in modern agricultural systems to ensure good harvests. Isocarbophos (ICP), with a potent acetylcholinesterase inhibitory effect is widely utilized to control a variety of leaf-eating and soil insects. However, the characteristics of the bioactivation and detoxification of ICP in humans remain unclear. In this study, the oxidative metabolism, esterase hydrolysis, and chiral inversion of ICP in human liver microsomes (HLMs) were investigated with the aid of a stereoselective LC/MS/MS method. The depletion of ICP in HLMs was faster in the absence of carboxylesterase inhibitor (BNPP) than in the presence of NADPH and BNPP, with t1/2 of 5.2 and 90 min, respectively. Carboxylesterase was found to be responsible for the hydrolysis of ICP, the major metabolic pathway. CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19 were all involved in the secondary metabolism pathway of desulfuration of ICP. Flavin-containing monooxygenase (FMO) did not contribute to the clearance of ICP. The hydrolysis and desulfuration of (±)ICP, (+)ICP, and (-)ICP in HLMs follow Michaelis-Menten kinetics. Individual enantiomers of ICP and its oxidative desulfuration metabolite isocarbophos oxon (ICPO) were found to be inhibitors of acetylcholinesterases at different extents. For example, (±)ICPO is more potent than ICP (IC50 0.031μM vs. 192μM), whereas (+)ICPO is more potent than (-)ICPO (IC50 0.017μM vs. 1.55μM). Given the finding of rapid hydrolysis of ICP and low abundance of oxidative metabolites presence in human liver, the current study highlights that human liver has a greater capacity for detoxification of ICP.

Keywords: enantiomers; enzyme kinetics; isocarbophos; isocarbophos oxon; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Animals
  • Carboxylesterase / antagonists & inhibitors
  • Carboxylesterase / metabolism*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacokinetics*
  • Cholinesterase Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Electrophorus
  • Enzyme Activation
  • Humans
  • Inactivation, Metabolic
  • Insecticides / chemistry
  • Insecticides / metabolism
  • Insecticides / pharmacokinetics*
  • Insecticides / pharmacology
  • Malathion / analogs & derivatives*
  • Malathion / chemistry
  • Malathion / metabolism
  • Malathion / pharmacokinetics
  • Malathion / pharmacology
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Recombinant Proteins / chemistry
  • Stereoisomerism


  • Cholinesterase Inhibitors
  • Insecticides
  • Recombinant Proteins
  • isocarbophos
  • Cytochrome P-450 Enzyme System
  • Carboxylesterase
  • Acetylcholinesterase
  • Malathion