Abstract
Age-dependent chlorpyrifos (CPF) metabolism was quantified by in vitro product formation in human hepatic microsomes (ages 13 days to 75 years) and plasma (ages 3 days to 43 years) with gas chromatography-mass spectrometry. Hepatic CPF cytochrome P450 desulfuration [CPF to chlorpyrifos-oxon (CPF-oxon)] and dearylation (CPF to 3,5,6-trichloro-2-pyridinol) Vmax values were 0.35 ± 0.21 and 0.73 ± 0.38 nmol · min−1 · mg microsomal protein −1 (mean ± S.D.), respectively. The mean (±S.D.) hepatic CPF-oxon hydrolysis (chlorpyrifos-oxonase [CPFOase]) Vmax was 78 ± 44 nmol · min−1 · mg microsomal protein −1. None of these hepatic measures demonstrated age-dependent relationships on a per microsomal protein basis using linear regression models. Ratios of CPF bioactivation to detoxification (CPF desulfuration to dearylation) Vmax values were consistent across ages. CPFOase in plasma demonstrated age-dependent increases on a volume of plasma basis, as did total plasma protein levels. Mean (±S.D.) CPF-oxon hydrolysis Vmax values for children <6 months of age and adults (≥16 years) were 1900 ± 660 and 6800 ± 1600 nmol · min−1 · ml−1, respectively, and at environmental exposure levels, this high- capacity enzyme is likely to be sufficient even in infants. Plasma samples were phenotyped for paraoxonase status, and frequencies were 0.5, 0.4, and 0.1 for QQ, QR, and RR phenotypes, respectively. These results will be integrated into a physiologically based pharmacokinetic and pharmacodynamic model for CPF and, once integrated, will be useful for assessing biological response to CPF exposures across life stages.
Footnotes
This work was supported by Dow AgroSciences, LLC.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038745.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- P450
- cytochrome P450
- CPF
- chlorpyrifos
- CPF-oxon
- chlorpyrifos-oxon
- CPFOase
- chlorpyrifos-oxonase
- GC-MS
- gas chromatography-mass spectrometry
- PON1
- paraoxonase
- ChE
- cholinesterase
- MTBSTFA
- N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide
- PND
- postnatal day
- ANCOVA
- analysis of covariance.
- Received February 14, 2011.
- Accepted April 26, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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