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Microsomal metabolism of trenbolone acetate metabolites: Transformation product formation and bioactivity.
Citation:
Michalsen, B., A. Kupsco, E. Uwimana, N. Pflug, N. Evans, E. Kolodziej, D. Schlenk, V. Wilson, H. Lehmler, AND D. Cwiertny. Microsomal metabolism of trenbolone acetate metabolites: Transformation product formation and bioactivity. SETAC, Orlando, FL, November 06 - 10, 2016.
Impact/Purpose:
Trenbolone acetate (TBA) is widely used in the US in animal feedlot operations and as a result is found in agriculturally impacted receiving waters. Beyond the three widely recognized TBA metabolites, little is known about other metabolites formed. In this study TBA was incubated with rat liver microsomes to evaluated metabolite formation via analytical chemistry. The extract containing the metabolite mixture produced was also tested in our in vitro MDA-kb2 assay to evaluated metabolite mixture bioactivity. the bioassay results suggest that the transformation products are generally less active than the parent compound which is important for the evaluation of potential environmental risks.
Description:
Trenbolone acetate (TBA) is a synthetic growth promoter widely used in animal agriculture, and its metabolites are suspected endocrine disrupting compounds in agriculturally impacted receiving waters. However, beyond the three widely recognized TBA metabolites (17-trenbolone, 17-trenbolone and trendione), little is known about other metabolites formed in vivo and subsequently discharged into the environment, with some evidence suggesting these unknown metabolites comprise a majority of the TBA mass dosed to the animal. Here, we explored the metabolism of the three known TBA metabolites using rat liver microsome studies. All TBA metabolites are transformed into a complex mixture of monohydroxylated products. Based on product characterization, the majority are more polar than the parent metabolites but maintain their characteristic trienone backbone. A minor degree of interconversion between known metabolites was also observed, as were higher order hydroxylated products with a greater extent of reaction. Notably, the distribution and yield of products were generally comparable across a series of variably induced rat liver microsomes, as well as during additional studies with human and bovine liver microsomes. Bioassays conducted with mixtures of these transformation products suggest that androgen receptor (AR) binding activity is diminished as a result of the microsomal treatment, suggesting that the transformation products are generally less potent than the parent TBA metabolites from which they were generated. Outcomes of this work are beneficial in attempting to more confidently assess the environmental occurrence and ecosystem risks associated with TBA use in animal agriculture. Disclaimer: This abstract does not necessarily reflect U.S. EPA policy.