The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol

Derek Simonsen; Jacob Heffelfinger; David M. Cwiertny; Hans-Joachim Lehmler

doi:10.1016/j.etap.2022.104008

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The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol

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The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol

Derek Simonsen, Jacob Heffelfinger, David M. Cwiertny and Hans-Joachim Lehmler

Environmental toxicology and pharmacology, Vol.96, pp.104008-104008

11/2022

DOI: 10.1016/j.etap.2022.104008

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https://pmc.ncbi.nlm.nih.gov/articles/PMC13033361/View

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Abstract

The metabolism and toxicity of current-use herbicide safeners remain understudied. We investigated the enantioselective metabolism of the safener benoxacor in Rhesus monkey subcellular fractions. Benoxacor was incubated with liver microsomes and cytosol from female and male monkeys (≤30 min). Benoxacor levels and enantiomeric fractions were determined with gas chromatography. Benoxacor was metabolized by microsomal cytochrome P450 enzymes (CYPs), cytosolic glutathione-S-transferases (GSTs), and microsomal and cytosolic carboxylesterase (CESs). CES-mediated microsomal metabolism followed the order males > females, whereas the CYP-mediated clearance followed the order females > males. CYP-mediated metabolism initially resulted in an enrichment of the second eluting benoxacor enantiomer (E2-benoxacor), whereas the first eluting benoxacor enantiomer (E1-benoxacor) was enriched after 10 or 30 min in female or male microsomal incubations. Benoxacor metabolism by GSTs was enantiospecific, with a total depletion of E1-benoxacor after approximately 20 min. Thus, the enantioselective metabolism of benoxacor by GSTs and CYPs may affect its toxicity. •Benoxacor was enantioselective metabolized by cytochrome P450 enzymes and carboxylesterase.•Benoxacor was enantiospecifically metabolized by cytosolic glutathione-S-transferases.•The scaled intrinsic clearance of benoxacor was highest for glutathione-S-transferases.•The predicted clearance of benoxacor by cytochrome P450 enzymes was sex-dependent.

Biotransformation

Carboxylesterase

Chiral

Cytochrome P450 enzyme

Enantiomer

Glutathione-S-transferase

Details

Title: Subtitle: The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol
Creators: Derek Simonsen - University of Iowa
Jacob Heffelfinger - Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA 52242, United States
David M. Cwiertny - University of Iowa
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA 52242, United States
Resource Type: Journal article
Publication Details: Environmental toxicology and pharmacology, Vol.96, pp.104008-104008
DOI: 10.1016/j.etap.2022.104008
ISSN: 1382-6689
eISSN: 1872-7077
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100000001, name: National Science Foundation, award: CBET-1335711, CBET-1702610, CBET-1703796, CHE-1609791; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000066, name: National Institute of Environmental Health Sciences, award: P30 ES005605
Language: English
Date published: 11/2022
Academic Unit: Center for Health Effects of Environmental Contamination; Civil and Environmental Engineering; Occupational and Environmental Health; Iowa Neuroscience Institute; Public Policy Center (Archive); Chemistry; Chemical and Biochemical Engineering
Record Identifier: 9984314360302771

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