bcrp/abcg2 substrates

Found insideA compendium of proven experimental approaches and strategies for studying the bioactivation, detoxification, tissue distribution, and elimination of xenobiotics in the metabolism and/or transport of various chemicals. Low resolution structural investigations have suggested that higher order oligomeric species are possible McDevitt et al (2006), but the functional relevance of this is not clear. A serotonin receptor agonist used to treat migraines and cluster headaches. Careers. An androgen used to treat low or absent testosterone. More than 80 polymorphisms in ABCG2 have been reported, with the most studied being the c.421C>A SNP in exon 5, which results in a p.Q141K substitution and lower protein expression (Table 1.2). A mixture of estrogens used in estrogen replacement therapy for menopause and hypoestrogenism, used in the treatment of various malignancies, and used in the treatment of postmenopausal osteoporosis. Variants of ABCG2 with impaired expression and/or transport function have been found as major determinants of gout develop-ment, as this transporter is a key player in the intesti-nal uric acid removal pathway [26–29]. Cells in a side population have distinguishing biological characteristics depending on the markers used in identifying them. Hematopoietic cells from Bcrp/ ani-mals are exquisitely sensitive to chemotherapeutic agents, such as mitoxantrone, that are BCRP substrates (12, 13). A number of ABCG2 SNPs have been found to influence the function and/or expression of the encoded protein. Leflunomide and A771726 as substrates of BCRP. Flavonoids with weak estrogenic activities are … Found insideIf the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. Synonyms: ABC15, ABCP, BCRP, BCRP1, BMDP, CD338, CDw338, EST157481, MGC102821, MRX, MXR, MXR1 Entrez Gene Link. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. Denise M.T. cancer resistance protein (Bcrp) (ABCG2). Corresponding Author. Optimization of dose and route of administration of the P-glycoprotein inhibitor, valspodar (PSC-833) and the P-glycoprotein and breast cancer resistance protein dual-inhibitor, elacridar (GF120918) as dual infusion in rats. Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. A pyrimidine synthesis inhibitor with anti-inflammatory and immunomodulatory properties used to treat patients with the relapsing-remitting form of multiple sclerosis. A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(-/-), Bcrp(-/-), and Mdr1a/1b(-/-)/Bcrp… To assess the possible role of BCRP in sex-dependent pharmacokinetics, we studied the in vivo disposition of several murine Bcrp1 substrates in male and female wild-type and Bcrp1 knockout mice. Substrates transported at a high rate turn on the ATPase, and thus stimulation of ATPase is indicative of the nature of the interaction.50 51 An actinomycin used to treat a wide variety of cancers. BSEP is an ATP-binding cassette (ABC) tr Found insideHandbook of Pharmacogenomics and Stratified Medicine is a comprehensive resource to understand this rapidly advancing field aiming to deliver the right drug at the right dose to the right patient at the right time. Monolayer efflux assays and vesicular transport assays have been extensively utilized in vitro. Disclaimer, National Library of Medicine Božina N, Ganoci L, Simičević L, Gvozdanović K, Domjanović IK, Fistrek Prlić M, Križ T, Borić Bilušić A, Laganović M, Božina T. Arh Hig Rada Toksikol. In addition to pregnancy-related steroid hormones and xenobiotics, growth factors affect ABCG2/BCRP expression. ABCG2—also known as breast cancer resistance protein (BCRP) or mitoxantrone-resistant protein (MXR) or placenta-specific ATP binding cassette transporter (ABCP)—is an ABC half-transporter with six transmembrane domains and only one ATP-binding domain. Found insideWith international experts sharing their experience and knowledge on these different aspects in the management of colorectal cancer, this book has this opportunity to offer all physicians treating colorectal cancer, as well as researchers, ... Meyer zu Schwabedissen et al. [164] ABCG2 also plays a role in disposition of other drugs, with the 421C>A variant reducing biliary excretion of rosuvastatin. There is currently no safety or efficacy data for use of tegaserol in men. Announcing our newly launched DrugBank Affiliate Partnerships for biotech and pharma consultants! Moreover, in the first decade, in vivo studies using Abcg2 knockout mice (Jonker et al., 2002) coupled with biochemical characterizations reveale… Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). Unable to load your collection due to an error, Unable to load your delegates due to an error. In one particular study, a subset of stem cells from primary neuroblastoma tumor cells found to be resistant to cytotoxics such as mitoxantrone were shown to express high levels of ABCG2 (Hirschmann-Jax et al., 2004). ABCG2 is also upregulated through aryl hydrocarbon receptor (AhR) (Ebert et al., 2005). Our Human BCRP Vesicles can be used to evaluate test compounds and drug interactions with BCRP in in vitro assays. Found inside – Page iiiThis book aims to provide an update on the advancements in the therapeutic arms race between cancer, clinicians and scientists alike to overcome resistance to targeted therapies. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Universität Freiburg im Breisgau, Freiburg im Breisgau, Germany, The Molecular Basis of Cancer (Fourth Edition), Drug efflux pumps in photodynamic therapy, Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy, Pharmacogenetics/Pharmacogenomics of Drug-Metabolizing Enzymes and Transporters, The Significance of ABC Transporters in Human Placenta for the Exposure of Fetus to Xenobiotics, Reproductive and Developmental Toxicology (Second Edition), Allikmets et al., 1998; Doyle et al., 1998, Doyle et al., 1998; Maliepaard et al., 2001, Kobayashi et al., 2005; Imai et al., 2002, Imai et al., 2002; Kobayashi et al., 2005, xPharm: The Comprehensive Pharmacology Reference, Current Challenges in Personalized Cancer Medicine, Moitra et al., 2011; Scharenberg et al., 2002, Li et al., 2011; Sun et al., 2010; Tabor et al., 2011; Yajima et al., 2009; Yanamoto et al., 2011, Chen et al., 2009, 2010; Okamoto et al., 2009; Zhang et al., 2010; Zhao et al., 2011, Chen et al., 2009; Li et al., 2011; Yajima et al., 2009, cells from ESCC specimens, which are enriched upon treatment with 5-FU or cisplatin, show increased expression of ABCA5 in addition to, Handbook of Pharmacogenomics and Stratified Medicine, Developing Solid Oral Dosage Forms (Second Edition). Prevention and treatment information (HHS). Side population is a term derived from flow cytometry, denoting a sub-population of cells that is distinct from the main population, on the basis of the markers employed. PMC In addition, genetic or epigenetic regulation of the ABCG2 expres- In addition, genetic or epigenetic regulation of the ABCG2 expres- A dopamine D2 receptor antagonist used in the treatment of acute and chronic schizophrenia, and in the prevention and treatment of postoperative nausea and vomiting in adults. BCRP (breast cancer resistance protein; ABCG2) is an important efflux transporter. A common mechanism is the overexpression of ABC exporters like P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) in cancer cells that limit the exposure to anticancer drugs. The breast cancer resistance protein (BCRP/ABCG2) and its murine homolog Bcrp1 belong to the ATP binding cassette (ABC) transmembrane drug transporter family. A selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women. Collectively, these results indicate that THC and 11-OH-THC are not substrates or inhibitors (at pharmacologically relevant concentrations) of either P-gp or BCRP. The ATP-binding cassette transporter G2 (ABCG2; also known as breast cancer resistance protein, BCRP) has been suggested to be involved in clinical multidrug resistance (MDR) in cancer like other ABC transporters such as ABCB1 ( P -glycoprotein). The AUC and peak concentration of rosuvastatin increased 2.4-fold in healthy individuals with the homozygous 421AA genotype compared to that in individuals with the 421CC genotype, but did not affect the elimination of t1/2, which signifies that 421C >A affects the intestinal absorption of rosuvastatin [120]. 2-CdA is frequently used for treatment of leukemia ( 12) and this is notable because Abcg2 (Bcrp) is expressed at higher levels in certain subtypes of leukemia ( 13). ABCG2 + populations show evidence for self-renewal, generating both ABCG2 + and ABCG2 − daughter cells during culture, and have a higher proliferative activity. Previous research has pointed to the estrogenic mycotoxin zearalenone as a potential substrate for BCRP. Keywords: Placentas with the 421A variant allele had lower ABCG2/BCRP protein levels than those with 421C (Kobayshi et al., 2005). High expression of BCRP was observed on the oocyte surface. This study investigated this based on pharmacokinetics using Mdr1a / 1b (−/−), Bcrp (−/−), and Mdr1a / 1b (−/−)/ Bcrp (−/−) mice. tubular injury. The most substantial clinical effects are likely to be for drugs that have a narrow therapeutic index and have a low bioavailability. 2015 Apr;43(4):490-509. doi: 10.1124/dmd.114.062174. Expert opinion: Clinical substrates display complex pharmacokinetics due to broad interaction profiles with multiple transporters and metabolic enzymes. ABCG2 is an ABC-transporter that homodimerizes at the plasma membrane and actively effluxes a range of substrates, including both cytotoxic compounds and fluorescent DNA binding Hoechst dyes (Sarkadi et al., 2004). MBECs expressed mRNA for the efflux pumps P-gp (ABCB1), BCRP (ABCG2) and multidrug resistance-associated protein-1, 2, 4, and 5 (ABCC1, 2, 4, 5), as shown in Figure 2a. One purine analogue, 2-chloro-2′-deoxyadenosine (2-CdA), is of particular relevance. A poly-ADP ribose polymerase inhibitor used to treat HER2-, BRCA mutated locally advanced or metastatic breast cancer. 0.011 for BCRP and 0.047± 0.014 for MDR1). A sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy. Found insideThis book highlights important techniques for cellular imaging and covers the basics and applications of electron tomography and related techniques. (2010) found that the three extracellular cysteines (592, 603, and 608) taking part in dimerization may all be mutated without losing multidrug resistance activity. The potent Abcg2 inhibitor Ko143 (Allen et al., 2002) was used as a positive control and comparison. Breast cancer resistant protein (BCRP/ABCG2) is expressed throughout the body including brain, liver, kidney, and small intestine and extrudes its substrates from cells. Specific mechanisms in drug resistance are reviewed and novel approaches are being proposed for therapeutic interventions. This volume is of general interest to scientists, clinicians, health care providers, and students. A fluoroquinolone antibiotic used to treat skin and skin structure infections.
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