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Published on: March 28, 2017
Human variation in CYP-specific chlorpyrifos metabolism
Edward L Croom1, Andrew D Wallace, Ernest Hodgson
1Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, United States.
Toxicology
|August 17, 2010
Summary
Individual differences in chlorpyrifos metabolism, specifically chlorpyrifos-oxon (CPO) production, were significant. This variability, linked to specific cytochrome P450 enzymes, may impact poisoning risk.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacogenetics
Background:
- Chlorpyrifos is an organothiophosphate insecticide metabolized by cytochrome P450 enzymes (CYPs).
- Bioactivation of chlorpyrifos to its neurotoxic metabolite, chlorpyrifos-oxon (CPO), varies among individuals.
- Understanding this variability is crucial for assessing chlorpyrifos toxicity risks.
Purpose of the Study:
- To investigate the inter-individual variability in chlorpyrifos bioactivation to CPO using human liver microsomes.
- To correlate CPO and 3,5,6-trichloro-2-pyridinol (TCP) production with specific CYP enzyme activities and genotypes.
- To determine the role of CYP2B6, CYP2C19, and CYP3A4 in chlorpyrifos metabolism.
Main Methods:
- Human liver microsomes from 17 donors were used to measure CPO and TCP production at varying chlorpyrifos concentrations (20 μM and 100 μM).
- Enzyme activities were assessed using specific substrates and chemical inhibitors (ketoconazole, ticlopidine).
- Correlation analyses were performed between metabolite formation and CYP activities; CYP2B6 genotype was also examined.
Main Results:
- Significant inter-individual variability (14- to 57-fold) in CPO production was observed, increasing with substrate concentration.
- TCP production also showed considerable variability (9- to 19-fold).
- CPO formation correlated with CYP2B6 activity at low concentrations and CYP3A4 at high concentrations; TCP production correlated with CYP3A4.
- CYP2B6 genotype did not significantly affect CPO formation.
Conclusions:
- Individual variations in chlorpyrifos metabolism, particularly CPO production, are substantial and linked to CYP2B6 and CYP3A4 activities.
- These metabolic differences highlight the need to consider individual variability when assessing chlorpyrifos exposure risks.
- The study confirms the critical roles of CYP2B6, CYP2C19, and CYP3A4 in chlorpyrifos bioactivation and detoxification.
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