You are here:
Metabolism of cyclic phenones in rainbow trout in vitro assays
Citation:
Serrano, J., M. Tapper, Rick Kolanczyk, B. Sheedy, T. Lahren, D. Hammermeister, J. Denny, M. Hornung, A. Kubatova, P. Kosian, J. Voelker, AND P. Schmieder. Metabolism of cyclic phenones in rainbow trout in vitro assays. XENOBIOTICA. Taylor & Francis, Inc., Philadelphia, PA, 50(2):115-131, (2019). https://doi.org/10.1080/00498254.2019.1596331
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 further exploring the role of metabolism in estrogenic activity modulation with the use of in vitro fish assays. Biotransformation data correlated to chemical exposure and potential adverse outcomes will facilitate development of additional in vitro and short-term in vivo assays needed to better prioritize chemicals for testing and support risk assessment at the USEPA, update and optimize metabolism simulators with validated mechanistic data, and provide insight into the differential sensitivity of species to chemical exposure. In addition, assessing the role of metabolites in cellular responses associated with endocrine disruption will provide USEPA with a means to advance methods for species extrapolation and improve understanding of interspecies homology and comparative toxicity.
Description:
Cyclic phenones are chemicals of interest to the USEPA and international community due to their potential for endocrine disrupting activity. Prior to this report, there was very limited information addressing metabolism of cyclic phenones by fish species and the potential for Estrogen Receptor (ER) binding and Vitellogenin (Vtg) gene activation by their metabolites. The main objectives of the current research were to characterize rainbow trout (rt) liver slice-mediated in vitro metabolism of model parent cyclic phenones exhibiting disparity between ER binding and ER-mediated Vtg gene induction, and to assess the metabolic competency of fish liver in vitro tests to help determine the chemical form (parent and/or metabolite) associated with the observed biological response. Biochemical strategies and high-throughput analytical methods (GC-MS, HPLC and LC-MS/MS) were applied to investigate the in vitro biotransformation of cyclobutyl phenyl ketone (CBP), benzophenone (DPK), cyclohexyl phenyl ketone (CPK) mostly in the absence of standards for metabolite characterization. It was concluded that estrogenic effects of the studied cyclic phenones are mediated by the parent chemical structure for DPK, but by active metabolites for CPK. A definitive interpretation was not possible for CBP and CBPOH (alcohol), although a contribution of both structures to gene induction is suspected.
