Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells.
Inflammation and infection may have the potential to increase the bioavailability of drugs. This effect could be because of a reduced metabolism of xenobiotics in the liver and/or the intestines, or because of alterations in small intestinal permeability, mucosal flow, and expression of drug efflux transporters such as P-glycoprotein (Pgp). To assess the impact on intestinal epithelium of some proinflammatory cytokines and macrophages on permeability and mRNA expression of CYP3A4 and MDRI (multidrug resistance, coding for Pgp), we used the Caco-2 cell line as a model. Exposure to proinflammatory cytokines and macrophages decreased the mRNA expression of CYP3A4 and increased the expression of MDR1 mRNA in the Caco-2 cells. In parallel, the cell layer permeability, as measured by sodium fluorescein flux, increased for all cytokine and macrophage treatments, whereas the effect on transepithelial electrical resistance (TEER) varied. Our findings suggest that inflammation and infection trigger several different cellular responses that may affect drug bioavailability; that is hampered CYP3A4 expression, increased permeability of the epithelial cell layer, and enhanced Pgp-mediated counteractive transport.
Bertilsson
P M
PM
Department of Health and Environment, Division of Medical Microbiology, Linköping, University, S-581 85 Linköping, Sweden. petbe@ihm.liu.se
Olsson
P
P
Magnusson
K E
KE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism; D018920:Coculture Techniques; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D019450:Genes, MDR / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human