Interactions between drugs and sulforaphane modulate the drug metabolism enzymatic system Katarzyna Lubelska 1 , Ma³gorzata Milczarek 1 , Karolina Modzelewska 1 , Jolanta Krzysztoñ-Russjan 2 , Krzysztof Fronczyk 3 , Katarzyna Wiktorska 1 Confocal Microscopy Laboratory, Department of Cell Biology, Vitamin Laboratory, Department of Biochemistry and Biopharmaceutics, National Medicines Institute, Che³mska 30/34, PL 00-725 Warszawa, Poland Faculty of Psychology, University of Finance and Management in Warsaw, Pawia 55, PL 01-420 Warszawa, Poland Correspondence: Katarzyna Wiktorska, e-mail: wiktorska@il.waw.pl Abstract: Background: Sulforaphane (SFN) is a potent chemopreventive agent, which is widely consumed in diet or as a diet supplement. It modulates the enzymes of II and III metabolism phase. In this paper, the influence of SFN and three commonly consumed drugs: furosemide, verapamil and ketoprofen on II and III metabolisms phase enzymes was studied. We have also investigated if the inter- actions between SFN and the drugs occur resulting in enzymatic system disturbances. Methods: The Caco-2 cells were incubated with SFN and drugs separately or in a mixture simultaneously or subsequently. The im- pact of the compounds on the cell viability and NADPH:quinine reductase (QR) activity was determined. The expression of glutathione-S-transferase (GST) isoenzymes GSTA3, GSTM1, P-glycoprotein (PgP) and multidrug resistance protein 1 (MRP1) genes was measured by qPCR method. Since these enzymes are regulated by Nrf2 pathway, the localization of Nrf2 (Nuclear erythroid 2-related factor) after exposure to the mixtures of SFN and the drugs was evaluated by confocal microscopy. Results: SFN was shown to interact antagonistically with the studied drugs. At most cases an increase in enzymatic activity and expression was observed. The most significant changes were observed in case of enzymes regulated by Nrf2: QR, GSTA1 and GSTA3 and also MRP1. PgP was shown to be not altered by the studied compounds. Cocnclusion: The interaction between SFN and furosemide, verapamil and ketoprofen modify the activity of enzymatic system involved in drug metabolism and transport . This may lead to drug effectiveness alteration and also to multidrug resistance (MDR) development. Key words: sulforaphane, ketoprofen, verapamil, furosemide, interactions, metabolism, enzymes Abbrevations: ABC – ATP-binding cassette, ARE – antioxi- dant response element, GSH – glutathione, GST – glutathione- S-transferase, ITC – isothiocyanate, Keap1 – Kelch-like ECH- associated protein 1, MDR – multidrug resistance, MRP – mul- tidrug resistance protein, Nrf2 – Nuclear erythroid 2-related factor, PgP – P-glycoprotein, QR – NADPH:quinine reductase, SFN – sulforaphane. Introduction In view of the growing interest in preventive medi- cine, an increase in the consumption of dietary sup- plements is observed. According to the National Health Interview Survey, in 1999, 9.9% of the Ameri- 1243