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Diazinon is activated by CYP2C19 in human liver
W A Kappers1, R J Edwards, S Murray
1Toxicology Unit, Section on Clinical Pharmacology, Faculty of Medicine, Imperial College, Du Cane Road, London W12 0NN, United Kingdom. WeKa@novonordisk.com
Toxicology and Applied Pharmacology
|November 16, 2001
Summary
This study identifies the primary human liver enzyme responsible for activating the pesticide diazinon. Cytochrome P450 2C19 (CYP2C19) is the major enzyme, with CYP1A2 playing a minor role in this critical metabolic pathway.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Phosphorothioate compounds, including the pesticide diazinon, are widely used in agriculture and domestic settings.
- The metabolic activation of diazinon to its toxic metabolite, diazoxon, in the human liver is a crucial process for understanding its toxicity.
Purpose of the Study:
- To elucidate the specific cytochrome P450 (P450) enzymes involved in the activation of diazinon to diazoxon in human liver.
- To characterize the kinetic parameters and identify the key P450 isoforms responsible for this metabolic transformation.
Main Methods:
- Human liver microsomes were used to study the kinetics of diazoxon formation from diazinon.
- Correlation analysis was performed between diazinon activation rates and the activities of various P450 probe substrates.
- The effects of specific P450 inhibitors were assessed on diazinon activation.
- Heterologously expressed human P450 enzymes were utilized to confirm the role of individual isoforms.
Main Results:
- Significant inter-individual variability in diazoxon formation rates was observed in human liver microsomes, suggesting multiple P450 enzyme involvement.
- Diazinon activation exhibited both high- and low-affinity components, with the high-affinity component correlating with CYP2C19 activity.
- CYP2C19 was identified as the most efficient enzyme in activating diazinon among tested heterologous P450s, followed by CYP3A4 and CYP1A2.
- Diazinon significantly inhibited hepatic microsomal S-mephenytoin 4'-hydroxylase and high-affinity phenacetin O-deethylase activities.
Conclusions:
- Cytochrome P450 2C19 (CYP2C19) is the predominant enzyme responsible for the activation of diazinon to diazoxon in the human liver.
- CYP1A2 and potentially CYP3A4 may contribute to diazinon activation, albeit to a lesser extent.
- Understanding the specific P450 enzymes involved is critical for assessing the toxicological risks associated with diazinon exposure.