Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker

Oswald A. Dadson, Corie A. Ellison, Steven T. Singleton, Lai Har Chi, Barbara P. McGarrigle, Pamela J Lein, Fayssal M. Farahat, Taghreed Farahat, James R. Olson

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0μg/g creatinine) were elevated to 34.5-3566μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516μM followed by 2B6 (Km=1.02μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility.

Original languageEnglish (US)
Pages (from-to)35-39
Number of pages5
JournalToxicology
Volume306
DOIs
StatePublished - Apr 5 2013

Fingerprint

Biomarkers
Cytochromes
Metabolism
Creatinine
Butyrylcholinesterase
Detoxification
Carboxylesterase
4-bromo-2-chlorophenol
profenofos
Liver Microsomes
Esterases
Acetylcholinesterase
Metabolites
Polymorphism
Agriculture
Pesticides
Liver
Cotton
Kinetics

Keywords

  • 4-Bromo-2-chlorophenol (BCP)
  • Cytochrome P450 (CYP)
  • Pooled human liver microsomes
  • Profenofos
  • Recombinant human CYPs

ASJC Scopus subject areas

  • Toxicology

Cite this

Dadson, O. A., Ellison, C. A., Singleton, S. T., Chi, L. H., McGarrigle, B. P., Lein, P. J., ... Olson, J. R. (2013). Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker. Toxicology, 306, 35-39. https://doi.org/10.1016/j.tox.2013.01.023

Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker. / Dadson, Oswald A.; Ellison, Corie A.; Singleton, Steven T.; Chi, Lai Har; McGarrigle, Barbara P.; Lein, Pamela J; Farahat, Fayssal M.; Farahat, Taghreed; Olson, James R.

In: Toxicology, Vol. 306, 05.04.2013, p. 35-39.

Research output: Contribution to journalArticle

Dadson, OA, Ellison, CA, Singleton, ST, Chi, LH, McGarrigle, BP, Lein, PJ, Farahat, FM, Farahat, T & Olson, JR 2013, 'Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker', Toxicology, vol. 306, pp. 35-39. https://doi.org/10.1016/j.tox.2013.01.023
Dadson, Oswald A. ; Ellison, Corie A. ; Singleton, Steven T. ; Chi, Lai Har ; McGarrigle, Barbara P. ; Lein, Pamela J ; Farahat, Fayssal M. ; Farahat, Taghreed ; Olson, James R. / Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker. In: Toxicology. 2013 ; Vol. 306. pp. 35-39.
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abstract = "Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0μg/g creatinine) were elevated to 34.5-3566μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516μM followed by 2B6 (Km=1.02μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility.",
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T1 - Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker

AU - Dadson, Oswald A.

AU - Ellison, Corie A.

AU - Singleton, Steven T.

AU - Chi, Lai Har

AU - McGarrigle, Barbara P.

AU - Lein, Pamela J

AU - Farahat, Fayssal M.

AU - Farahat, Taghreed

AU - Olson, James R.

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N2 - Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0μg/g creatinine) were elevated to 34.5-3566μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516μM followed by 2B6 (Km=1.02μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility.

AB - Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0μg/g creatinine) were elevated to 34.5-3566μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516μM followed by 2B6 (Km=1.02μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility.

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