Selective metabolism of E-3,4-bis(4-ethylphenyl)hex-3-ene in rat liver microsomes |
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Authors: | Eric J. Fabian Manfred Metzler |
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Affiliation: | (1) Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe, P.O. Box 6980, 76128 Karlsruhe, Germany;(2) Present address: BASF Aktiengesellschaft, Experimental Toxicology and Ecology, Carl-Bosch-Strasse 38, 67056 Ludwigshafen am Rhein, Germany |
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Abstract: | The synthetic stilbene derivative E-3,4-bis(4-ethylphenyl)hex-3-ene (E-DE-BPH) has been proposed as a potential anticancer drug with a new mode of action. We report here on the in vitro metabolism of E-DE-BPH in liver microsomes of rats and pigs. The formation of five metabolites, which could be separated on a reverse-phase HPLC column with UV detection, was observed in microsomal incubations. To facilitate the structural identification of these metabolites, two different deuterium-labeled forms of E-DE-BPH were synthesized. By comparing the mass spectra obtained for the metabolites of unlabeled E-DE-BPH and of the two deuterated forms, it could be demonstrated that E-DE-BPH was oxidized by liver microsomes exclusively at the benzylic positions of the molecule. The major metabolite was identified as E-3-(4-(1-hydroxyethyl)phenyl)-4-(4-ethylphenyl)hex-3-ene. Four minor metabolites were formed from the major metabolite, either by hydroxylation at the other benzylic position to yield a bishydroxylated metabolite, or by oxidation of the hydroxyl group to form E-3-(4-acetylphenyl)-4-(4-ethylphenyl)hex-3-ene. The latter compound was also obtained by chemical oxidation of the monohydroxylated metabolite of E-DE-BPH. Since no products containing hydroxyl groups at the aromatic rings or at other aliphatic sites of the molecule were detected, a surprisingly selective oxidative metabolism of E-DE-BPH appears to occur with rat and pig liver microsomes. |
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Keywords: | In vitro metabolism Liver microsomes 3,4-Bis(4-ethylphenyl)hex-3-ene Stilbene |
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