RTP: One Effective Platform to Probe Reactive Compound Transformation Products and Its Applications for a Reactive Plasticizer BADGE

Reactive
compounds, such as covalent toxicants/drugs, have their
ubiquitous occurrences and are known to react with protein or DNA
in human beings, but their reactions with endogenous metabolites are
rarely understood. Currently, a viable platform is demanded for discovering
their reaction products since their efficacy/toxicity may be altered
after the reaction. We aim to develop a platform for identifying unknown
abiotic or biotransformation products for these reactive compounds.
Based on stable isotope-labeling (SIL) metabolomics, we have developed
a novel and robust analytical platform, reactive compound transformation
profiler (RTP), which can automatically analyze preannotated high-resolution
mass spectrometry (LC-HRMS) data sets and uncover probable transformation
products. Generally, RTP consists of four complementary steps: (1)
selecting peak pairs of light and heavy-labeled products, (2) defining
the “core structure mass” for possible reaction search,
(3) constructing an endogenous metabolite reaction database, and (4)
developing algorithms to propose the potential transformation products
by searching against the database with a single-/multiple-site reaction.
Its performance was validated using the reactive plasticizer bisphenol
A diglycidyl ether (BADGE) in several sample matrices. This platform
enabled the identification of novel transformation products while
also demonstrating its capacity to filter out the false-positive signals
and provide product annotation. The RTP is freely accessible at https://github.com/FangLabNTU/Reactive-Compound-Transformation-Profiler-RTP-.