Genistein is a natural isoflavone regarded as a useful agent for prophylaxis or treatment of many diseases: i.e. osteoporosis, menopause, cardiovascular disease, and cancer. During recent years new derivatives of genistein, which show better pharmacological characteristics comparing to the parent isoflavone, were synthesized in different laboratories. The promising class of genistein derivatives, with potential anticancer properties comprise of glycoconjugates in which a sugar moiety is separated from the isoflavone skeleton via an alkyl chain containing two, three or five carbon atoms. These compounds are further divided into two classes: the derivatives substituted at C7, and the derivatives substituted at C4’ position of genistein. Previous studies showed that this class of compounds inhibits proliferation of cancer cell in vitro at the concentration several-fold lower than genistein through inhibition of the cell cycle [1-2].

The aim of this work was to determine the relationship between the structure of the linker and the position of genistein substitution, and bioavailability of the glycoconjugates and their metabolism in the intestine. In our studies we used Caco-2 cell line, cultured in 24- well plates with porous membranes until the tight monolayer was obtained. The integrity of the monolayer was estimated by transepithelial electrical resistance (TEER)  measurement. The concentration of genistein derivatives in medium collected from apical and basolateral chambers was determined using a Dionex UHPLC system connected to a 4000 Q TRAP triple quadrupole linear ion trap mass spectrometer. Chromatography was performed using a C18 ACE column (150×4.6 mm, 3.0 µlm). Isocratic conditions were applied: 30% of 0,1% aqueous formic acid and 70% of acetonitrile, the flow rate was set at 0,8 ml/min and sample injecion volume was 5µl. The MS conditions: the parameters dependent on the source and the compound were tuned up for individual derivatives.  Final analysis was performed in selected reaction monitoring mode, using the precursor ions and the corresponding product ions.  For determining the metabolites, the full scan mode was used (scanned mass ranged between 50 and 700 m/z).   

Our result indicate that transport and metabolism of genistein derivatives depend on their chemical structure. Both, structure of the linker between the sugar moiety and genistein, and position of genistein molecule substitution are important determinants of bioavailability of the compounds. Moreover, we determined that genistein derivatives described in this work were transformed in Caco-2 cells into glucuronide metabolites. 

Acknowledgements:

References:

[1] Rusin, J. Zawisza-Puchałka, K. Kujawa, A. Gogler-Pigłowska, J. Wietrzyk, M. Świtalska, M. Głowala-Kosińska, A. Gruca, W. Szeja, Z. Krawczyk, G. Grynkiewicz, Bioorganic & Medicinal Chemistry 19 (2011) 295-305.

[2] Byczek A., Zawisza-Puchalka J., Gruca A., Papaj K., Grynkiewicz G., Rusin M., Szeja W., Rusin A. Journal of Chemistry,  Volume 2013 (2013), Article ID 191563, 12 pages.

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