Journal
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
Volume 179, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.pestbp.2021.104964
Keywords
Uniconazole; Rat liver microsomes; Enantioselective metabolism; LC-MS; MS spectrometry; Molecular docking
Categories
Funding
- National Natural Science Foundation of China [92056113]
- Natural Science Foundation of Guangdong Province [2018A030313193]
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This study investigated the stereochemistry of uniconazole enantiomers and their metabolism in rat liver microsomes. Through vibrational circular dichroism spectroscopy and chiral column analysis, it was found that (R)-uniconazole exhibited preferential metabolism in the rat liver microsomes compared to (S)-uniconazole, which was further confirmed by molecular docking studies showing higher binding affinity to cytochrome CYP2D2. This work provides valuable insights for the risk assessment of uniconazole on human health and the environment.
In this work, stereochemistry of uniconazole enantiomers and their metabolism behaviors in rat liver microsomes have been researched. Significance analysis has been applied in data processing. Absolute configurations of uniconazole enantiomers were identified through vibrational circular dichroism spectroscopy. According to their elution order from the chiral column using the CO2-methanol (80:20, v/v) mixture, two eluted fractions were determined to be (R)-uniconazole and (S)-uniconazole, respectively. A high-efficient and sensitive LC-MS/MS chiral analysis method was established for investigating the metabolism of uniconazole enantiomers in rat liver microsomes. The metabolic half-life of (R)-uniconazole (38.7 min) in rat liver microsomes was half that of (S)-enantiomer (74.5 min), and maximum velocity of metabolism, Michaelis constant of metabolism as well as the intrinsic metabolic clearance of (R)-uniconazole were significantly higher than (S)-enantiomer (p < 0.05), which indicated that (R)-uniconazole was preferentially metabolized in rat liver microsomes. By the virtue of molecular docking, (R)-uniconazole exhibited a higher binding affinity to cytochrome CYP2D2 than (S)-enantiomer, which corroborated well with the metabolism results. This work will shed light on the risk assessment of uniconazole toward human health and the ecological environment.
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