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 detoxificatio n. Because many drugs that are metabolized by human cytochromes P450 ( CYP) 3A4 and 3A5 are also transported by the drug efflux pump P-glycop rotein, we determined whether expression of these proteins was altered by a variety of drugs in a cell line derived from a human colon adeno carcinoma, 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 tr eatment with many drugs, including rifampicin, phenobarbital, clotrima zole, reserpine, and isosafrole. However, there were some exceptions b ecause P-glycoprotein was up-regulated by midazolam and nifedipine, wh ereas CYP3A4 was not. CYP3A5, which is also constitutively expressed i n these cells, remained unchanged with most drug treatments but was up -regulated by reserpine and clotrimazole. The apparent coordinated coe xpression of the CYP3A gene family and P-glycoprotein in the LS180 cel ls suggests that for common orally administered drugs, P-glycoprotein may play an important role in net drug absorption and drug/drug intera ctions of shared CYP3A4/P-glycoprotein substrates.