posted on 2023-12-20, 22:07authored byMatthias
J. A. Vink, Jimmy Alarcan, Jonathan Martens, Wybren Jan Buma, Albert Braeuning, Giel Berden, Jos Oomens
Toxicological assessments of newly developed agrochemical
agents
consider chemical modifications and their metabolic and biotransformation
products. To carry out an in silico hazard assessment, understanding
the type of chemical modification and its location on the original
compound can greatly enhance the reliability of the evaluation. Here,
we present and apply a method based on liquid chromatography–mass
spectrometry (LC–MS) enhanced with infrared ion spectroscopy
(IRIS) to better delineate the molecular structures of transformation
products before in silico toxicology evaluation. IRIS facilitates
the recording of IR spectra directly in the mass spectrometer for
features selected by retention time and mass-to-charge ratio. By utilizing
quantum-chemically predicted IR spectra for candidate molecular structures,
one can either derive the actual structure or significantly reduce
the number of (isomeric) candidate structures. This approach can assist
in making informed decisions. We apply this method to a plant growth
stimulant, digeraniol sinapoyl malate (DGSM), that is currently under
development. Incubation of the compound in Caco-2 and HepaRG cell
lines in multiwell plates and analysis by LC–MS reveals oxidation,
glucuronidation, and sulfonation metabolic products, whose structures
were elucidated by IRIS and used as input for an in silico toxicology
assessment. The toxicity of isomeric metabolites predicted by in silico
tools was also assessed, which revealed that assigning the right metabolite
structure is an important step in the overall toxicity assessment
of the agrochemical. We believe this identification approach can be
advantageous when specific isomers are significantly more hazardous
than others and can help better understand metabolic pathways.