Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun 7:181-187

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 02/2005; 326(1):181-7. DOI: 10.1016/j.bbrc.2004.11.012
Source: PubMed


Breast cancer resistance protein (Bcrp/Abcg2) is a member of the ABC transporter family. The purpose of this study was to quantify Bcrp mRNA in rat and mouse tissues, and to determine whether there are gender differences in Bcrp mRNA expression. Rat Bcrp mRNA levels were high in intestine and male kidney, and intermediate in testes. Mouse Bcrp expression was highest in kidney, followed by liver, ileum, and testes. Male-predominant expression of Bcrp was observed in rat kidney and mouse liver. Furthermore, gonadectomy and hypophysectomy experiments were conducted to determine whether sex steroids and/or growth hormone are responsible for Bcrp gender-divergent expression patterns. Male-predominant expression of Bcrp in rat kidney appears to be due to the suppressive effect of estradiol, and male-predominant expression of Bcrp in mouse liver appears to be due to the inductive effect of testosterone.

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    • "BCRP has a broad substrate specificity and mediates efflux of numerous substances, including food toxicants like benzo(a)pyrene, bisphenol A (BPA) and several mycotoxins (Ebert et al., 2007; van Herwaarden et al., 2006), as well as substances/nutrients important for normal health, like vitamins (van Herwaarden et al., 2007) and hormones (Gram et al., 2009). BCRP is commonly expressed in tissues involved in drug and xenobiotic absorption (small and large intestinal epithelia), distribution (the blood–brain and placental barriers) and elimination (kidney, liver) (Gutmann et al., 2005; Maliepaard et al., 2001; Tanaka et al., 2005). BCRP is also expressed in the apical membranes of different polarized cell models used for transport studies, e.g. "
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    ABSTRACT: The efflux transporter breast cancer resistance protein (BCRP/ABCG2) decrease intestinal absorption of many food toxicants. Oleic acid increases absorption of the specific BCRP substrate mitoxantrone (MXR), and also BCRP gene expression in human intestinal Caco-2 cells, suggesting that oleic acid affect the BCRP function. Here, we investigated the effect of oleic acid on intestinal absorption of MXR in mice. Mice were orally dosed with 2.4g oleic acid/kg b.w. and 1mg MXR/kg b.w. and sacrificed 30, 60, 90 or 120min after exposure, or were exposed to 0.6, 2.4 or 4.8g oleic acid/kg b.w. and 1mg MXR/kg b.w. and sacrificed 90min after exposure. Mice were also treated with Ko143 together with MXR and sacrificed after 60min, as a positive control of BCRP-mediated effects on MXR absorption. Absorption of MXR increased after exposure to oleic acid at all doses, and also after exposure to Ko143. Intestinal BCRP gene expression tended to increase 120min after oleic acid exposure. Our results in mice demonstrate that oleic acid decreases BCRP-mediated efflux, causing increased intestinal MXR absorption in mice. These findings may have implications in humans, concomitantly exposed to oleic acid and food contaminants that, similarly as MXR, are substrates of BCRP. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 06/2015; 237(2). DOI:10.1016/j.toxlet.2015.06.009 · 3.26 Impact Factor
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    • "The probes were synthesized by Integrated DNA Technologies (Coralville, IA). The probe sets for mouse Cyp1a1, 2b10, 3a11, 4a14, and NADPH:quinone oxidoreductase (Nqo1) (Cheng et al., 2005b), organic anion transporting polypeptides (Oatp) (Cheng et al., 2005a), multidrug resistance-associated proteins (Mrp) (Maher et al., 2005b), organic anion transporters (Oat) (Buist and Klaassen, 2004), concentrative nucleoside transporters (Cnt) (Lu et al., 2004), equilibrative nucleoside transporters (Ent) (Lu et al., 2004), heme oxygenase 1 (Ho-1) (Aleksunes et al., 2005), sodiumphosphate cotransporter (Ntcp), bile salt export pump (Bsep) (Cheng et al., 2007), breast cancer resistance protein (Bcrp) (AbcG2) (Tanaka et al., 2005), Cyp7a1, ATP-binding cassette transporters (Abca1, Abcg5, Abcg8) (Dieter et al., 2004), organic cation transporters (Oct) (Alnouti et al., 2006), peptide transporters (Pept) (Lu and Klaassen, 2006), pregnane-X receptor (PXR), multidrug resistance proteins (Mdr), organic solute transporters a and b (Osta, Ostb), Niemann-pick C1 like 1 transporter (Npc1l1), sodium-phosphate cotransporter 1 (Npt1), apical sodium dependent bile acid transporter (Asbt) (Cheng and Klaassen, 2006), sulfotransferases (Sult) (Alnouti and Klaassen, 2006), glutathione S-transferases (Gst) (Knight et al., 2007), and UDP-glucuronosyltransferases (Ugt) (Buckley and Klaassen, 2007) have been reported. Probe sequences of mouse Cpr are shown in "
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    ABSTRACT: Cytochrome P450 enzymes (Cyps) play important roles in first-pass metabolism in both the intestine and liver. NADPH-cytochrome P450 oxidoreductase (Cpr) is an essential electron transfer protein required for microsomal CYP activity. Mice with conditional knockout of Cpr in hepatocytes develop normally and survive even with complete loss of liver microsomal CYP activity. The current studies were performed to determine whether alternative drug-metabolizing pathways increase in an attempt to maintain whole-body homeostasis. In addition to liver, Cpr is mainly expressed in tissues such as lung, kidney, and gastrointestinal tract. In livers of H-Cpr-null mice, there is a marked increase in mRNA expression of phase-I enzymes (Aldh1a1, 1a7, 3a2; Ces1b2, 2a6, and 2a12), antioxidant enzymes (Ho-1, Nqo1, and epoxide hydrolase), phase-II enzymes (Ugt1a9; Gsta1/2, m3, m4, m6, t1, and t3; and Sult1a1 and 1d1), and drug transporters (Oatp1a4, Oct3, Mate1, Mdr1a, and Mrp3 and 4). In addition, glucuronide-conjugated bilirubin concentrations are doubled in serum of H-Cpr-null mice. Both CAR and Nrf2 protein in nuclei are higher in livers of H-Cpr-null mice, indicating that CAR and Nrf2 are activated. In the small intestine of H-Cpr-null mice, mRNA expression of Cyp3a11 and Mdr1a, two genes critical for intestinal first-pass metabolism, are markedly up-regulated. In addition, nutrient (Pept1) and cholesterol (Npc1l1) transporters are induced in the small intestine of H-Cpr-null mice. In conclusion, in H-Cpr-null mice, adaptive regulation of alternative detoxification genes in liver and small intestine appear to partially compensate for the loss of microsomal Cyp function in liver.
    Drug metabolism and disposition: the biological fate of chemicals 08/2014; 42(11). DOI:10.1124/dmd.114.060053 · 3.25 Impact Factor
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    • "Breast cancer resistance protein (BCRP) is a drug transporter, which belongs to ATP-binding cassette transporter subfamily G. High levels of BCRP mRNA are predominantly observed in kidney, intestines, liver, and cerebral cortex of male rats (Tanaka et al., 2005). The observed high levels of BCRP mRNA in kidney suggest that BCRP is important in urinary excretion of its substrates (Mizuno et al., 2004). "
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    ABSTRACT: Previous studies on diabetes have reported controversial results with regard to transporters in liver. The present study aimed to explore changes in hepatic breast cancer resistance protein (BCRP) expression and functions, as well as the possible underlying mechanisms, in type 2 diabetic patients, type 1 (streptozotocin-induced), and type 2 (Goto Kakizaki) diabetic rats. Protein and mRNA levels of human (h) and rat (r) BCRP were investigated using Western blot and quantitative polymerase chain reaction analyses. Functions of liver rBCRP were evaluated using rosuvastatin. Sandwich cultured rat hepatocytes (SCRH) were cultured with d-glucose, insulin, or oleic acid for 72h, and rBCRP mRNA was detected. The effect of oleic acid on rBCRP function in SCRH was also investigated using rosuvastatin. Results showed that liver rBCRP mRNA levels decreased to 20% in type 1 diabetic rats, whereas that in diabetic patients and GK rats significantly increased threefold and twentyfold, respectively. No changes were observed in h/rBCRP protein levels of type 2 diabetic patients and GK rats. The functions of rBCRP significantly declined in type 1 diabetic rats but showed no significant changes in GK rats. The data from SCRH indicated that d-glucose decreased rBCRP mRNA level to 60%. Oleic acid increased rBCRP mRNA in SCRH by approximately eightfold but decreased rBCRP function to 50%. Therefore, h/rBCRP expression and functions were oppositely regulated in type 1 and type 2 diabetes mellitus subjects. Alternations in d-glucose, insulin, and free fatty acid levels in plasma might contribute to the changes in h/rBCRP expression and functions.
    European journal of pharmacology 12/2013; 724(1). DOI:10.1016/j.ejphar.2013.12.008 · 2.53 Impact Factor
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