The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes.
In this paper we investigated the effects of several drugs used in transplant medicine, i.e. cyclosporine A, tacrolimus, rapamycin, everolimus, mycophenolate mofetil, fluvastatin and rosuvastatin, on the expression of major drug-metabolizing enzymes in human hepatocytes. Moreover, we tested the ability of these drugs to affect transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon receptor (AhR). We found that most of tested compounds did not induce expression of CYP1A1/1A2/3A4/2A6/2B6/2C9 mRNAs in human hepatocytes. Slight induction was observed for CYP2A6/2C9 mRNAs and CYP2A6 protein in the rapamycin-treated hepatocytes. Decrease of CYP2A6 and CYP2B6 proteins was observed in rosuvastatin-treated cells. Mycophenolate mofetil antagonized the effects of dexamethasone on GR but it potentiated the action of dioxin on AhR. Induction of CYP1A1 mRNA in HepG2 cells by dioxin was modestly antagonized by mycophenolate mofetil, while the induction by benzo[a]pyren or S-omeprazole was significantly potentiated by this drug. In general, tested compounds can be considered safe in the terms of possible drug-drug interaction caused by induction of drug-metabolizing cytochromes P450. Nevertheless, mycophenolate mofetil is of possible concern and its combination with drugs, environmental pollutants or food constituents, which activate AhR, may represent a significant toxicological risk.
Department of Cell Biology and Genetics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, Olomouc CZ-783 71, Czech Republic. Electronic address: radim.vrzal@email.cz.
Radim
R
Vrzal
Department of Cell Biology and Genetics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, Olomouc CZ-783 71, Czech Republic.
Ondrej
O
Zenata
Department of Surgery, University Hospital, I.P. Pavlova 6, 775 15 Olomouc, Czech Republic.
Petr
P
Bachleda
Department of Cell Biology and Genetics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, Olomouc CZ-783 71, Czech Republic.
Zdenek
Z
Dvorak
D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015262:Xenobiotics / Q000378:metabolism
D007155:Immunologic Factors; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011965:Receptors, Glucocorticoid; D015262:Xenobiotics; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases
Cytochrome P450; Drug interaction; Human hepatocytes; Transplant drugs; Xenoreceptors