gene expression was found to decrease along the length of the gastrointestinal tract, with highest levels found in the duodenum and least expensive levels found in the rectum70

gene expression was found to decrease along the length of the gastrointestinal tract, with highest levels found in the duodenum and least expensive levels found in the rectum70. over 66kb and contains 16 exons and 15 introns. In cell collection models, high levels of expression are often accompanied by rearrangements including chromosome 4 or by gene amplification4, 5. The promoter has been reported to contain estrogen6, hypoxia7 and progesterone response8 elements that have been shown MYSB to control GSK598809 gene expression and a peroxisome proliferator-activated receptor (PPAR) response element upstream of the ABCG2 gene has also been recognized9. GSK598809 The promoter is usually methylated in selected cell lines; treatment with demethylating brokers will increase expression. In other cell types, increased promoter acetylation following exposure to deacetylase inhibitors will increase gene expression10. Cytokines and growth factors11,12 as well as microRNAs13, 14 have been shown to have variable effects on gene expression. The ABCG2 protein is made up of 655 amino GSK598809 acids and runs as a 72 kDa protein in reducing conditions. It is has one N-terminal nucleotide binding domain name (NBD) and 6 C-terminal transmembrane segments comprising one transmembrane domain name (TMD); this is in a reverse configuration compared to other ABC transporters where the NBD is at the C-terminus and the TMD is at the N-terminus. ABCG2 is considered a half-transporter as most transporters have at least 2 NBDs and 2 TMDs. ABCG2 is found in the G family of transporters, which is made up of only half transporters. As a half transporter, ABCG2 must dimerize to form a functional transporter. Substrates and Inhibitors of ABCG2 ABCG2, much like Pgp, has proven to be a promiscuous transporter in that multiple compounds of different chemical classes are numbered among its substrates. It is of course best GSK598809 known for its ability to transport chemotherapeutic brokers, with mitoxantrone, topotecan and SN-38 (the active metabolite of irinotecan) being among the most analyzed substrates. However, ABCG2 has also been shown to confer resistance to organic anions, such as the glucuronide conjugate of SN-3815. In this regard, there is overlapping substrate specificity with both Pgp and the MRPs. Other substrates include flavopiridol16; camptothecins such as irinotecan (and its active metabolite SN-38)17, 18, 9-aminocamptothecin19 and diflomotecan20; indolocarbazoles including edotecarin21 and becatecarin22; antifolates such as methotrexate and some of its polyglutamylated forms23, GW1843 and raltitrexed24 as well as others; photosensitizers such as 2-(1-hexyloxethyl)-2-devinylpyropheophorbide a (HPPH)25, benzoporphyrin derivative monoacid ring A25 and pyropheophorbide a methyl ester26; and kinase inhibitors such as gefitinib27, imatinib28, nilotinib29 and JNJ-770662130. A number of other substrates unrelated to malignancy treatment have also been explained including uric acid31, HMG-CoA reductase inhibitors32, antivirals33, antibiotics34, 35, carcinogens36, 37 and dihydropyridines38 as well as D-luciferin39. A selected list of substrates is usually provided in Table 1. Table 1 Select substrates of ABCG2 Mitoxantrone1Camptothecins????Topotecan121????Irinotecan (and SN-38)122????9-aminocamptothecin19Tyrosine Kinase Inhibitors????Imatinib28????Gefitinib27????Nilotinib29????Dasatinib123Carcinogens????Aflatoxin B137????Benzo[a]pyrene sulfate124????2-amino-3-methylimidazo[4,5-f]quinoline (IQ)37????3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)37????2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP)36Porphyrins and Photosensitizers????Pheophorbide a125????Pyropheophorbide a methyl ester26????Chlorin e626????Protoporphyrin IX25????Benzoporphyrin derivative monoacid ring A25????2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a (HPPH)25Antibiotics????Cephalosporins126????Fluoroquinolones35Antifolates23, 24HMG-CoA reductase inhibitors32, 127Thiosemicarbazones113, 128Imidazoacridinones129Naphthoquinones130Pancratistatin113Sulfasalazine131Cimetidine132Flavopiridol16Uric Acid31Glyburide133Becatecarin22Riboflavin134 Open in a separate window The search for ABCG2 inhibitors began with the discovery that fumitremorgin C (FTC) could reverse resistance in the mitoxantrone-selected S1-M1-3.2 cell line from which ABCG2 was cloned40. Some of the first ABCG2 inhibitors recognized were also Pgp inhibitors, such as elacridar (GF120918)41, biricodar (VX-710)42, dofequidar (MS-209)43 and tariquidar (XR-9576)44. Other inhibitors include dihydropyridines45, tyrosine kinase inhibitors46, flavonoids47, 48, rotenoids49 and botryllamides50. Other inhibitors of ABCG2 are provided in Table 2. Table 2 Select inhibitors of ABCG2 Diketopiperazines????Fumitremorgin C135????Ko14373????Tryprostatin A136Immunosupressants????Cyclosporin A137????Tacrolimus138????Sirolimus138Tyrosine Kinase Inhibitors????Gefitinib46????Erlotinib139????Imatinib140????Nilotinib29????Lapatinib141????Sunitinib142????Vandetanib143P-glycoprotein Inhibitors????Elacridar41????Tariquidar44????Biricodar42????Dofequidar43Flavonoids????Genistein144????Naringenin144????Kaempferol144????Chrysin47????6-prenylchrysin48Antivirals145Calcium Channel Blockers146Botryllamides50Novobiocin147Curcumin148Bisindolylmaleimides149Indolocarbazoles149Dimethoxyaurones150Chalcone Derivatives151Acridone Derivatives152Nonprenylated Rotenoids49Cannabinoids153 Open in a separate window In the case of several molecularly targeted anticancer brokers, it has been hard to determine whether the drugs are substrates or inhibitors. Evidence for both types of conversation has been presented in several reports for imatinib, nilotinib, and gefitinib27C29, 51, 52. It is clear that this drugs interact with ABCG2, and careful studies suggest a concentration dependence C a substrate at low concentrations and inhibitory properties at high concentrations. In patients, oral gefitinib has been shown to increase plasma levels of GSK598809 orally administered topotecan (discussed below), suggesting in vivo activity as an inhibitor. Pharmacokinetic Effects of ABCG2 Single Nucleotide Polymorphisms Several.