Selective metabolism of E-3,4-bis(4-ethylphenyl)hex-3-ene in rat liver microsomes.
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.
Fabian
Eric J
EJ
Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe, P.O. Box 6980, 76128 Karlsruhe, Germany. eric.fabian@basf-ag.de
Metzler
Manfred
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism*; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013267:Stilbenes / Q000138:chemical synthesis / Q000378:metabolism*; D013552:Swine
D000970:Antineoplastic Agents; C522375:E-3,4-bis(4-ethylphenyl)hex-3-ene; D013267:Stilbenes; D020111:Chlorodiphenyl (54% Chlorine)