Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.
Xenobiotics frequently induce proteins involved in their detoxification. Because many drugs that are metabolized by human cytochromes P450 (CYP) 3A4 and 3A5 are also transported by the drug efflux pump P-glycoprotein, we determined whether expression of these proteins was altered by a variety of drugs in a cell line derived from a human colon adenocarcinoma, LS180/WT, and its adriamycin-resistant subline, LS180/AD50. P-glycoprotein and CYP3A4 were constitutively expressed in both LS180/AD50 and LS180/WT cells, and both proteins were up-regulated after treatment with many drugs, including rifampicin, phenobarbital, clotrimazole, reserpine, and isosafrole. However, there were some exceptions because P-glycoprotein was up-regulated by midazolam and nifedipine, whereas CYP3A4 was not. CYP3A5, which is also constitutively expressed in these cells, remained unchanged with most drug treatments but was up-regulated by reserpine and clotrimazole. The apparent coordinated coexpression of the CYP3A gene family and P-glycoprotein in the LS180 cells suggests that for common orally administered drugs, P-glycoprotein may play an important role in net drug absorption and drug/drug interactions of shared CYP3A4/P-glycoprotein substrates.
Schuetz
E G
EG
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Beck
W T
WT
Schuetz
J D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000230:Adenocarcinoma / Q000378:metabolism*; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D003022:Clotrimazole / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008874:Midazolam / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D010672:Phenytoin; D003907:Dexamethasone; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D003022:Clotrimazole; D008874:Midazolam; D012293:Rifampin; D010634:Phenobarbital