The pyrimidine analog 5-fluorouracil (5-FU) is an essential drug for metastatic carcinomas of gastrointestinal, breast, ovary, head and neck tumors.1-4) 5-FU-based combination chemotherapies have been applied for the treatment of tumors 2,5,6) ; for example, the FOLFIRI (5-FU, leucovorin and irinotecan) regimen has been a standard chemotherapy for colorectal cancer. 7) Randomized trials have demonstrated improvements in progression-free and overall survival when irinotecan (CPT-11) has been added to fluorouracil and leucovorin in the initial treatment of patients with metastatic colorectal cancer.6) The most commonly observed toxicities associated with irinotecan are neutropenia, diarrhea, myelosuppression, and alopecia. [7][8][9] Irinotecan is a derivative of the natural alkaloid camptothecin which is converted to an active metabolite, SN-38. SN-38 is metabolized predominantly in the liver, where it is inactivated by glucuronidation and excreted through the biliary system. It has been reported that carboxylate forms of SN38-Glu and SN-38 are transported by multidrug resistance protein 2 (Mrp2), suggesting that variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in biliary excretion of the metabolites contributes to interpatient variability in CPT-11 toxicity.10)The family of ATP binding cassette (ABC) transporters, for example, p-glycoprotein (P-gp), Mrp2 and breast cancer resistance protein (Bcrp), has important roles in the detoxification and excretion of xenobiotics.11,12) An Mrp isoform, Mrp2, has functions in the terminal excretion of cytotoxic and carcinogenic substances, and plays an important role in detoxification and chemoprevention. [11][12][13][14] Mrp2 is important clinically as it modulates the pharmacokinetics of many drugs, and its expression and activity are also altered by certain drugs and disease states.14) Alterations in Mrp2 expression and/or function could have a variety of clinically important effects. Altered Mrp2 function can change the clearance of many clinically important drugs. 13)There is accumulated evidence that medical drugs, toxins and health care supplements affect the expression levels of Mrp2 [14][15][16] ; however, the effect of 5-FU on the expression of Mrp2 is not clear. Here we report the effect of 5-FU treatment on the expression of Mrp2 in rats. We also investigated the effect of 5-FU treatment on mRNA expression of nuclear receptors: constitutive androstane receptor (CAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), and retinoid X receptor (RXR). The phosphorylation levels of c-jun in the kidney and liver were evaluated. It is known that the promoter region of Mrp2 contains an AP1 recognition site, which is bound with the heterodimer of c-jun and fos. [17][18][19] MATERIALS AND METHODSReagents A mouse monoclonal antibody specific for anti-multidrug resistance-related protein cMOAT/MRP2 (M 2 III-6), anti-glyceraldehyde-3-phosphate dehydrogenase (6C5), anti-b actin (AC-74), anti-P-glycoprotein (C219), and anti-breast c...