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Environmental Photochemistry of Altrenogest: Photoisomerization to a Bioactive Product with Increased Environmental Persistence via Reversible Photohydration

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journal contribution
posted on 29.06.2016, 00:00 by Kristine H. Wammer, Kyler C. Anderson, Paul R. Erickson, Sarah Kliegman, Marianna E. Moffatt, Stephanie M. Berg, Jackie A. Heitzman, Nicholas C. Pflug, Kristopher McNeill, Dalma Martinovic-Weigelt, Ruben Abagyan, David M. Cwiertny, Edward P. Kolodziej
Despite its wide use as a veterinary pharmaceutical, environmental fate data is lacking for altrenogest, a potent synthetic progestin. Here, it is reported that direct photolysis of altrenogest under environmentally relevant conditions was extremely efficient and rapid (half-life ∼25 s). Photolysis rates (observed rate constant kobs = 2.7 ± 0.2 × 10–2 s–1) were unaffected by changes in pH or temperature but were sensitive to oxygen concentrations (N2-saturated kobs = 9.10 ± 0.32 × 10–2 s–1; O2-saturated kobs = 1.38 ± 0.11 × 10–2 s–1). The primary photoproduct was identified as an isomer formed via an internal 2 + 2 cycloaddition reaction; the triplet lifetime (8.4 ± 0.2 μs) and rate constant (8 × 104 s–1) of this reaction were measured using transient absorption spectroscopy. Subsequent characterization determined that this primary cycloaddition photoproduct undergoes photohydration. The resultant photostable secondary photoproducts are subject to thermal dehydration in dark conditions, leading to reversion to the primary cycloaddition photoproduct on a time scale of hours to days, with the photohydration and dehydration repeatable over several light/dark cycles. This dehydration reaction occurs more rapidly at higher temperatures and is also accelerated at both high and low pH values. In vitro androgen receptor (AR)-dependent gene transcriptional activation cell assays and in silico nuclear hormone receptor screening revealed that certain photoproducts retain significant androgenic activity, which has implications for exposure risks associated with the presence and cycling of altrenogest and its photoproducts in the environment.