The influence of soybean extract on the expression level of selected drug transporters, transcription factors and cytochrome P450 genes encoding phase I drug-metabolizing enzymes

Abstract

Objective: Soybean phytoestrogens, such as genistein and daidzein, reduce climacteric symptoms and the risk of certain chronic diseases such as cancer and cardiovascular diseases. Despite their widespread use in functional foods and dietary supplements, there is very little data available on their safety and herb-drug interactions, especially with antineoplastic agents. Hence, the aim of our study was to assess the effects of soybean extracts on the expression level of CYP genes and their transcriptional factors. We also investigated the effect of soybean on the mRNA level of transporters, such as P-glycoprotein (MDR1) and multidrug resistance-associated proteins (MRP1, MRP2). Materials and methods: Wistar rats were fed a standardized soybean extract (100 mg/kg, p.o.). cDNA was synthesized from total RNA isolated from different tissues (liver and intestinal epithelium) using reverse transcription. Gene expression level was analyzed by RT-PCR method. Results: We demonstrated a significant increase of CYP1A1 mRNA level (by 89%, p=0.002 and 125%, p=0.004) as compared with the control group. An increase of AHR and CAR expression after 10 days was also observed (by 60%, p<0.001 and 52%, p>0.05, respectively). Additionally, an inductive effect for CYP2D1 by 22% (p=0.008), Mdr1a by 267% (p<0.0001), Mdr1b by 86% (p<0.0001), Mrp1 by 9-fold (p<0.0001), Mrp2 by 83% (p<0.0001) in the liver and for Mrp2 by 35% (p<0.001) in the intestinal epithelium, was evaluated. A significant decrease of mRNA level was observed for CYP3A1 (human CYP3A4) in the liver and Mdr1b in the intestinal epithelium. Moreover, we also showed a slight decrease in the amount of mRNA for CAR, PXR and ARNT after 3 days. Conclusions: Our results suggest that Glycine max may change the expression level of CYPs, especially CYP3A4 and CYP1A1, involved in biotransformation of xenobiotics (drugs, procarcinogens) and may participate in clinically significant interactions with drugs metabolized by these enzymes. Moreover, an increase of CYP1A1 (homologue to human CYP1A1) mRNA level may not only reduce the carcinogenicity of foreign compounds, but may also activate some compounds to their carcinogenicity. In case of transporters, it is considered that an increase of their expression in the body may lead to increased fetoprotection. Also, it may reduce both, the exposure of sensitive tissues (e.g. brain, placenta) to xenobiotics and treatment effectiveness of certain diseases. Hence, the search for a safe substance that could effectively modulate transporter activity, especially in the treatment of certain hormone -dependent disorders. e.g. osteoporosis and breast cancer, occurring mainly in postmenopausal period, continues.