These findings suggest that ABCC11 confers resistance to MTA by enhancing efflux of the intracellular anti-cancer drug

These findings suggest that ABCC11 confers resistance to MTA by enhancing efflux of the intracellular anti-cancer drug. They further analyzed the relationship between gene manifestation and MTA sensitivity of 13 adenocarcinoma cell lines. 538G A within the apocrine phenotype, individuals response to nucleoside-based chemotherapy, and the potential risk of breast tumor. and and and and genes are related with axillary osmidrosis [13-15] and gout risk [16-18], respectively. Some additional ABC transporter genes will also be implicated in, or are candidates for, additional metabolic inherited diseases (http://nutrigene.4t.com:80/humanabc.htm). With this context, mutations and genetic polymorphisms in ABC transporter genes are considered important biomarkers for analysis of inherited diseases and prediction of the risk of drug-induced adverse reactions or response to chemotherapy. Among such human being ABC transporters, with this review article we will address human being ABCC11 to discuss the potential effect of its genetic polymorphisms within the physiological function, breast tumor risk, and individuals response to nucleoside-based chemotherapy. 2.?Finding OF Human being GENE In 2001, three research organizations, including us, independently cloned two novel ABC transporters named ABCC11 and ABCC12 from your cDNA library of human being adult liver [19-21]. These two genes have been found to be located on human being chromosome 16q12.1 Tyk2-IN-3 inside a tail-to-head orientation having a separation range of about 20 kb (Fig. (?1A1A)). The expected amino acid sequences of both gene products show a high similarity to the people of ABCC4 and ABCC5, suggesting that they have the typical structure of full ABC transporter (Fig. (?1B1B)). However, there is no putative mouse or rat orthologous gene related to human being [22]. This fact shows that is not an orthologous gene but rather a paralogous gene generated by gene duplication in the human being genome. Tyk2-IN-3 On the other hand, and its orthologous genes are found in different varieties including humans, primates, and rodents [22]. Open in a separate windowpane Fig. (1) (A) The genomic constructions of and genes on human being chromosome 16q12.1. The cytogenetic location of the gene as well as the constructions of exons and introns were analysed by BLAST searches on the human being genome. The gene is definitely encoded by a -68 kb gene consisting of 30 exons. A non-synonymous SNP: 538G A (Gly180Arg), an earwax determinant, is in the exon 4 of gene. (B) Schematic illustration of ABCC11 structure and hitherto known non-synonymous SNPs. ABCC11 has a total of 12 transmembrane (TM) areas and two intracellular ATP-binding cassettes. Asn838 and Asn844 residing in an extracellular loop between transmembrane helices TM7 and TM8 are [21] shown high levels of ABCC11 mRNA in breast cancer. The improved manifestation of ABCC11 crazy type (WT) in breast cancer might be related with low levels of effectiveness of chemotherapy, as discussed later on with this review. When transfected exogenously, the ABCC11 WT protein was Tyk2-IN-3 localized in the apical membrane of Madin-Darby canine kidney cells strain II (MDCK II) cells [23]. The substrate specificity of ABCC11 WT was characterized in more detail by an transport assay Rabbit Polyclonal to ZNF280C with plasma membrane vesicles prepared from pig LLC-PK1 cells transfected with an ABCC11 WT manifestation vector [24]. Their assay shown that ABCC11 WT is able to transport a variety of lipophilic anions, including cyclic nucleotides, glutathione conjugates such as leukotriene C4 (LTC4) and S-(2,4-dinitrophenyl)-glutathione (DNP-SG), steroid sulfates such as estrone 3-sulfate (E13S) and dehydroepiandrostenedione 3-sulphate (DHEAS), glucuronides such as estradiol 17–D-glucuronide (E217G), monoanionic bile acids glycocholate and taurocholate, and folic acid and its analog methotrexate (MTX) (Fig. (?2A2A)). Kinetic analyses suggest that cGMP and DHEAS are good substrates for ABCC11 (Table ?11) [23, 24]. Open in a separate windows Fig. (2) (A). Chemical structures of classical substrates of ABCC11. cAMP (cyclic adenosine monophosphate), cGMP (cyclic guanosine monophosphate), LTC4 (leukotriene C4), DNP-SG (S-(2,4-dinitrophenyl)-glutathione), E13S (estrone 3-sulfate), DHEAS (dehydroepiandrosterone 3-sulfate), and E217G (estradiol 17–D-glucuronide). (B) Anticancer drugs that are transported by ABCC11. MTA (pemetrexed), MTX, (methotrexate), Ara-C (Cytosine arabinoside), PMEA (9-(2-phosphonyl-methoxyethyl)adenine) are substrate for ABCC11. 5-fluoro-2-deoxyuridine 5-monophosphate (FdUMP) is an active metabolite of 5-FU (5-fluorouracil) and transported by ABCC11. Table 1 Kinetic Parameters for ABCC11-Mediated Transport 2005 [35]DHEAS13.034.9Chen 2005 [24]21.0370.0Bortfeld 2006 [23]E217G62.962.0Chen 2005 [24]E1S3150.0-Bortfeld 2006 [23]MTX957.0317.0Chen 2005 [24] Open in a separate window 3.?REGULATION OF ABCC11 GENE EXPRESSION In 2004 Bieche [25] reported that ABCC11 was up-regulated in estrogen receptor- -positive breast tumors, as compared with normal breast.