In Vitro Age-Dependent Enzymatic Metabolism of Chlorpyrifos and Chlorpyrifos-Oxon in Human Hepatic Microsomes and Chlorpyrifos-Oxon in Plasma

Smith, Jordan N.; Timchalk, Charles; Bartels, Michael; Poet, Torka S.

doi:10.1124/dmd.111.038745

Cited by 27 publications

(19 citation statements)

References 35 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At time of collection, prenatal samples were split with some of the tissue placed in RNA Later [quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis], and the remainder flash frozen (ABPP and proteomic analyses) and stored at -80°C. Additional human liver microsome samples obtained from a commercial source (XenoTech, LLC, Lenexa, KS), and reported by Smith et al (2011), were included in this study to extend the enzyme analyses through neonatal and adult developmental ages (sample metadata can be found in Supplemental Dataset 1; available metadata for each sample is rather disparate, and therefore we chose not to include it in our statistical analyses or data interpretation). The Institutional Review Board of Pacific Northwest National Laboratory approved all sample transfer procedures.…”

Section: Methodsmentioning

confidence: 99%

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Sadler

Nandhikonda

Webb-Robertson

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Cytochrome P450s are oxidative metabolic enzymes that play critical roles in the biotransformation of endogenous compounds and xenobiotics. The expression and activity of P450 enzymes varies considerably throughout human development; the deficit in our understanding of these dynamics limits our ability to predict environmental and pharmaceutical exposure effects. In an effort to develop a more comprehensive understanding of the ontogeny of P450 enzymes, we employed a multi-omic characterization of P450 transcript expression, protein abundance, and functional activity. Modified mechanism-based inhibitors of P450s were used as chemical probes for isolating active P450 proteoforms in human hepatic microsomes with developmental stages ranging from early gestation to late adult. High-resolution liquid chromatography-mass spectrometry was used to identify and quantify probe-labeled P450s, allowing for a functional profile of P450 ontogeny. Total protein abundance profiles and P450 rRNA was also measured, and our results reveal life-stage-dependent variability in P450 expression, abundance, and activity throughout human development and frequent discordant relationships between expression and activity. We have significantly expanded the knowledge of P450 ontogeny, particularly at the level of individual P450 activity. We anticipate that these results will be useful for enabling predictive therapeutic dosing, and for avoiding potentially adverse and harmful reactions during maturation from both therapeutic drugs and environmental xenobiotics.

show abstract

Section: Methodsmentioning

confidence: 99%

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Sadler

Nandhikonda

Webb-Robertson

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Studies in humans have also shown that serum PON1 activity is very low at birth and increases over time, reaching a plateau between 6 months and a few years of age, depending on the study (Augustinsson and Barr, 1963; Ecobichon and Stephens, 1973; Mueller et al 1983; Cole et al 2003; Chen et al 2003; Holland et al 2006; Huen et al 2010; Smith et al 2011). PON1 activity may be even lower before birth, as indeed indicated by data showing a 24% lower activity in premature babies (33-36 weeks of gestation) compared to term babies (Ecobichon and Stephens, 1973), and by very low levels of PON1 expression in human fetal liver (Parker-Katiraee et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity

et al. 2013

View full text Add to dashboard Cite

Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon and chlorpyrifos. PON1 activity is highest in liver and in plasma. Human PON1 displays two polymorphisms in the coding region (Q192R and L55M) and several polymorphisms in the promoter and the 3’-UTR regions. The Q192R polymorphism imparts differential catalytic activity toward some OP substrates, while the polymorphism at position –108 (C/T) is the major contributor of differences in the levels of PON1 expression. Both contribute to determining an individual's PON1 “status”. Animal studies have shown that PON1 is an important determinant of OP toxicity. Administration of exogenous PON1 to rats or mice protects them from the toxicity of specific OPs. PON1 knockout mice display a high sensitivity to the toxicity of diazoxon and chlorpyrifos oxon, but not of paraoxon. In vitro catalytic efficiencies of purified PON192 alloforms for hydrolysis of specific oxon substrates accurately predict the degree of in vivo protection afforded by each isoform. Evidence is slowly emerging that a low PON1 status may increase susceptibility to OP toxicity in humans. Low PON1 activity may also contribute to the developmental toxicity and neurotoxicity of OPs, as shown by animal and human studies.

show abstract

“…Metabolic pathways for bioactivation and detoxification of CPF (Smith et al , 2011). AChE, acetylcholinesterase; CYP450, cytochrome P450.…”

mentioning

confidence: 99%

Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict In Vivo Red Blood Cell Acetylcholinesterase Inhibition Following Exposure to Chlorpyrifos in the Caucasian and Chinese Population

Zhao

Kamelia

Boonpawa

et al. 2019

Toxicological Sciences

View full text Add to dashboard Cite

Organophosphates have a long history of use as insecticides over the world. The aim of the present study was to investigate the interethnic differences in kinetics, biomarker formation, and in vivo red blood cell acetylcholinesterase inhibition of chlorpyrifos (CPF) in the Chinese and the Caucasian population. To this purpose, physiologically based kinetic models for CPF in both the Chinese and Caucasian population were developed, and used to study time- and dose-dependent interethnic variation in urinary biomarkers and to convert concentration-response curves for red blood cell acetylcholinesterase inhibition to in vivo dose-response curves in these 2 populations by reverse dosimetry. The results obtained revealed a marked interethnic difference in toxicokinetics of CPF, with lower urinary biomarker levels at similar dose levels and slower CPF bioactivation and faster chlorpyrifos-oxon detoxification in the Chinese compared with the Caucasian population, resulting in 5- to 6-fold higher CPF sensitivity of the Caucasian than the Chinese population. These differences might be related to variation in the frequency of single-nucleotide polymorphisms for the major biotransformation enzymes involved. To conclude, the interethnic variation in kinetics of CPF may affect both its biomarker-based exposure assessment and its toxicity and risk assessment and physiologically based kinetic modeling facilitates the characterization and quantification of these interethnic variations.

show abstract

In Vitro Age-Dependent Enzymatic Metabolism of Chlorpyrifos and Chlorpyrifos-Oxon in Human Hepatic Microsomes and Chlorpyrifos-Oxon in Plasma

Cited by 27 publications

References 35 publications

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity

Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict In Vivo Red Blood Cell Acetylcholinesterase Inhibition Following Exposure to Chlorpyrifos in the Caucasian and Chinese Population

Contact Info

Product

Resources

About