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TDK conference 2015

Effect of flavonoids on cytochrome P450 activity in porcine intestinal epithelial cells
Kovács Dóra - year 4
SzIU, Faculty of Veterinary Science, Department of Pharmacology and Toxicology
Supervisor: Dr. Orsolya Farkas


Cytochrome P450 enzymes have a remarkable role in the metabolism of drugs and other xenobiotics; therefore they are always in focus of pharmacokinetic studies. CYP enzymes have an important effect on drug’s bioavailability, especially in case of oral administration. Oxidation of several drugs and food components catalysed by the same CYP isoenzyme can lead to drug-drug and drug-food interactions. There are chemicals that can inhibit or induce the CYP enzymes’ catalytic activity, which can also cause changes in the drugs’ effective dose and toxicity. Greatest quantity of cytochrome P450 enzymes can be found in the liver. Nevertheless, the intestinal CYP garniture also contributes to the metabolism of clinically important drugs. Our research focused on the effects of selected flavonoids (apigenin and its trimethylated analogue, apigenin-trimethylether) on the intestinal CYP enzymes, because flavonoids tend to be an increasing part of dietary supplements nowadays, due to their beneficent effects on many diseases.

In the experiments, porcine intestinal epithelial cells (IPEC J2) were used. Cells were growed on 24-well cell culture plates. After the cell monolayer was formed, apigenin (25 and 50μM) and apigenin-trimethylether (25 μM) was administered on some of them. Other cells stayed untreated, as control. Others were treated with a known inducer (phenobarbital, 1mM), and known inhibitors (naphtoflavone 50μM + ketoconazole 25μM). The CYP1A1, CYP1A2 and CYP3A4 activities were measured by chemiluminescent assay. Simultaneous treatment of enterocytes with apigenin and antipyrine was also performed in order to test possible drug interactions.

The inhibitor mix significantly decreased the CYP3A4 activity, and the inducer increased the enzymatic activity, compared to the control values. Apigenin in both concentration, and apigenin-trimethylether as well worked as a significant inhibitor (p < 0.5). The higher concentration of apigenin had a more efficient inhibitory effect than the lower one (p < 0.1). There was no significant difference between the inhibitory effect of apigenin-trimethylether and apigenin at the same dose. However, apigenin-trimethylether combined with the inducer, was significantly a more potent inhibitor, than the apigenin combined with the inducer. Antipyrine decreased the enzymatic activity, which effect was enhanced, when antipyrine and apigenin were administered simultaneously.

In conclusion, our results suggest that both apigenin and its trimethylated derivative can inhibit the intestinal cytochrome P450 activity, accurately the CYP3A4, which has the most important role in the metabolism of clinically important drugs. Further investigations should focus on the intestinal metabolism in other species, and afterwards, in vivo studies should be done in this topic.

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