title: Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: W T
authors.initials: WT
authors.lastname: Beck
authors.forename: J D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: 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
chemical_list: 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