Journal article
Benoxacor is enantioselectively metabolized by rat liver subcellular fractions
Chemico-biological interactions, Vol.330, pp.109247-109247
10/01/2020
DOI: 10.1016/j.cbi.2020.109247
PMID: 32866466
Abstract
This study investigated the enantioselective metabolism of benoxacor, an ingredient of herbicide formulations, in microsomes or cytosol prepared from female or male rat livers. Benoxacor was incubated for ≤30 min with microsomes or cytosol, and its enantioselective depletion was measured using gas chromatographic methods. Benoxacor was depleted in incubations with active microsomes in the presence and absence of NADPH, suggesting its metabolism by hepatic cytochrome P450 enzymes (CYPs) and microsomal carboxylesterases (CESs). Benoxacor was depleted in cytosolic incubations in the presence of glutathione, consistent with its metabolism by glutathione S-transferases (GSTs). The depletion of benoxacor was faster in incubations with cytosol from male than female rats, whereas no statistically significant sex differences were observed in microsomal incubations. The consumption of benoxacor was inhibited by the CYP inhibitor 1-aminobenzotriazole, the CES inhibitor benzil, and the GST inhibitor ethacrynic acid. Estimates of the intrinsic clearance of benoxacor suggest that CYPs are the primary metabolic enzyme responsible for benoxacor metabolism in rats. Microsomal incubations showed an enrichment of the first eluting benoxacor enantiomer (E1-benoxacor). A greater enrichment occurred in incubations with microsomes from female (EF = 0.67 ± 0.01) than male rats (EF = 0.60 ± 0.01). Cytosolic incubations from female rats resulted in enrichment of E1-benoxacor (EF = 0.54 ± 0.01), while cytosolic incubations from male rats displayed enrichment of the second eluting enantiomer (E2-benoxacor; EF = 0.43 ± 0.01). Sex-dependent differences in the metabolism of benoxacor in rats could significantly impact ecological risks and mammalian toxicity. Moreover, changes in the enantiomeric enrichment of benoxacor may be a powerful tool for environmental fate and transport studies.
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•Benoxacor is metabolized by rat the hepatic cytochrome P450 system and carboxylesterases in vitro.•Benoxacor is metabolized by hepatic glutathione S-transferases in vitro.•The in vitro metabolism of benoxacor is sex-dependent in rats.•Benoxacor is enantioselectively metabolized by different drug metabolizing enzymes.
Details
- Title: Subtitle
- Benoxacor is enantioselectively metabolized by rat liver subcellular fractions
- Creators
- Derek Simonsen - Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, 52242, United StatesDavid M Cwiertny - IIHR Hydroscience and Engineering, The University of Iowa, Iowa City, IA, 52242, United StatesHans-Joachim Lehmler - Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, 52242, United States
- Resource Type
- Journal article
- Publication Details
- Chemico-biological interactions, Vol.330, pp.109247-109247
- DOI
- 10.1016/j.cbi.2020.109247
- PMID
- 32866466
- NLM abbreviation
- Chem Biol Interact
- ISSN
- 0009-2797
- eISSN
- 1872-7786
- 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
- 10/01/2020
- Academic Unit
- Center for Health Effects of Environmental Contamination; Civil and Environmental Engineering; Occupational and Environmental Health; Iowa Neuroscience Institute; Public Policy Center (Archive); Chemical and Biochemical Engineering
- Record Identifier
- 9984000925102771
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