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Characterization and analysis of estrogenic cyclic phenone metabolites produced in vitro by rainbow trout liver slices using GC-MS, LC-MS and LC-TOF-MS
Citation:
Serrano, J., Rick Kolanczyk, M. Tapper, T. Lahren, N. Dongari, D. Hammermeister, Pat Kosian, P. Schmieder, B. Sheedy, K. Challis, AND A. Kubatova. Characterization and analysis of estrogenic cyclic phenone metabolites produced in vitro by rainbow trout liver slices using GC-MS, LC-MS and LC-TOF-MS. Journal of Chromatography B. Elsevier Science Ltd, New York, NY, 1126-1127:1-12, (2019). https://doi.org/10.1016/j.jchromb.2019.121717
Impact/Purpose:
The present research contributed to an overall effort to develop a comprehensive program to evaluate the potential adverse effects of chemicals on vertebrate endocrine systems by advancing metabolic product identification and metabolic pathway elucidation to complement metabolism studies addressing estrogenic activity modulation with the use of in vitro fish assays. Metabolite identification data correlated to chemical exposure and metabolic pathways will facilitate development of additional in vitro and short-term in vivo assays needed to prioritize chemicals for testing and support risk assessment at the USEPA, update metabolism simulators with new mechanistic data, and provide insight into the differential sensitivity of species to chemical exposure.
Description:
The identity of main metabolites produced in vitro by rainbow trout (rt) liver slices was investigated for the model cyclic phenones benzophenone (DPK), cyclohexyl phenyl ketone (CPK) and cyclobutyl phenyl ketone (CBP). While only one metabolite was observed for DPK and CBP (benzhydrol and CBPOH, respectively), nine (M1-M9) metabolites were detected for CPK. In absence of standards, CPK metabolites were identified by combining gas chromatography-mass spectrometry (GC-MS) with and without derivatization, liquid chromatography (LC) with tandem MS, and LC with high resolution time of flight (ToF) MS spectra information. Furthermore, LC fractionation allowed to find relationships between LC- and GC-MS data needed to assess substitution patterns. It was determined that CPK is metabolized by phase I oxidation of the cyclohexyl ring and not the phenyl group as predicted by metabolism models. CPK metabolites M1 and M2 (MW 186), were proposed to be cyclohexenyl-derivatives. Also, M6-M9 were confirmed as hydroxylated metabolites (MW 204), with the potential for undergoing phase II conjugative metabolism to glucuronides and sulfates. Finally, M3, M4 and M5 were identified as cyclohexanone-derivatives (MW 202), resulting from limited redox interconversion of their hydroxylated pairs M8, M6 and M7, respectively.
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DOI: Characterization and analysis of estrogenic cyclic phenone metabolites produced in vitro by rainbow trout liver slices using GC-MS, LC-MS and LC-TOF-MS