ABCMdb

PMID: 18673259

Nakamura T, Yamamori M, Sakaeda T
Pharmacogenetics of intestinal absorption.
Curr Drug Deliv. 2008 Jul;5(3):153-69., [PubMed]

Sentences

No. Mutations Sentence Comment

33 ABCC2 p.Arg1150His ABCC2 p.Ile1173Phe Two mutations 3517A>T and 3449G>A, predicting the substitution Ile1173Phe and Arg1150His, respectively, impaired the transport of carboxyfluorescein by ABCC2, while the 3517A>T mutation induced weaker ABCC2 expression and mislocation to the ER [39, 41]. Login to comment 34 ABCC2 p.Arg768Trp Arg768Trp induced by 2302C>T resulted in deficient maturation and impaired sorting, whereas Glu1382Arg induced by 4145A>G caused deficient transport [40]. Login to comment 35 ABCC2 p.Lys677Arg An artificial mutation, Lys677Arg (2030A>G), introduced into the Walker A motif of nucleotide-binding domain (NBD) 1, which has not been found in DJS patients, also resulted in deficient maturation and impaired sorting. Login to comment 36 ABCC2 p.Arg768Trp ABCC2 p.Val417Ile ABCC2 p.Ser789Phe ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr ABCC2 p.Ala1450Thr Hirouchi and colleagues evaluated the cellular location and function of ABCC2 Val417Ile (1249G>A), Arg768Trp (2302C>T), Ser789Phe (2366C>T), and Ala1450Thr (4348G>A) variants in LLC-PK1 cells, finding that Ser789Phe and Ala1450Thr mutations caused less expression and mislocation [51]. Login to comment 69 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Volk and co-workers reported that methotrexate resistance correlated with ABCG2 expression in cell lines expressing the wild-type transporter, whereas the Arg482Thr and Arg482Gly variants were more resistant to mitoxantrone and less resistant to methotrexate, than expected from their ABCG2 expression levels using drug-selected and ABCG2-transfected cell lines [78]. Login to comment 76 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Among the SNPs identified so far, two nonsynonymous SNPs, 34G>A and 421C>A, in the coding region, resulting in Val12Met and Gln141Lys, respectively, are relatively frequently identified and well-studied. Login to comment 77 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Honjo et al. sequenced 90 genomic DNA samples and identified Val12Met and Gln141Lys at a frequency of 12.2% and 6.1%, respectively [86]. Login to comment 78 ABCG2 p.Gln141Lys ABCG2 p.Val12Met The Val12Met and Gln141Lys polymorphisms were also identified in a sequence analysis of ABCG2 cDNA clones isolated from 11 human tumor cell lines and were confirmed to have allelic frequencies of 19.0% and 26.6%, respectively, by a genomic DNA analysis in 124 Japanese [85]. Login to comment 81 ABCG2 p.Gln141Lys Kondo and coworkers showed that the expression level of Gln141Lys ABCG2 was approximately 30-40% that of wild-type ABCG2 in membrane vesicles prepared from HEK293 cells infected with a recombinant adenovirus [94]. Login to comment 83 ABCG2 p.Val12Met ABCC2 p.Val417Ile ABCC2 p.Lys1299Gln ABCC2 p.Arg353His ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu ABCC2 p.Asn718Ser ABCC2 p.Leu849Arg ABCC2 p.Asp333Gly ABCC2 p.Arg1181Leu ABCC2 p.Pro1291Leu ABCC2 p.Ile1036Thr ABCC2 p.Ile670Thr ABCC2 p.Thr486Ile ABCC2 p.Glu893Gln ABCC2 p.Lys495Glu ABCC2 p.Met246Leu ABCC2 p.Asn1063Ser ABCC2 p.Ile982Val ABCC2 p.Phe562Leu In Vitro Studies Associated with Common SNPs of Drug Transporter Genes Exon Polymorphism Effect dbSNP Cell Expression Function Reference ABCC2 Exon 1 -24C>T 5`-UTR rs717620 116A>T Tyr2Phe rs927344Exon 2 159A>G synonymous rs17222596 Exon 7 736A>C Met246Leu rs17222744 Exon 8 998A>G Asp333Gly rs17222674 Exon 9 1058G>A Arg353His rs7080681 1219C>T synonymous rs17216198 1249G>A Val417Ile rs2273697 LLC-PK1 Protein (n.s.) Membrane localization (n.s.) Transport activity (n.s.) Hirouchi et al. [51] 1434G>T synonymous 1434G>A synonymous rs4267009 Exon 10 1457C>T Thr486Ile rs17222589 Exon 11 1483A>G Lys495Glu rs17222561 Exon 13 1686T>G Phe562Leu rs17216233 2009T>C Ile670Thr rs17222632Exon 16 2073C>A synonymous rs17222624 Exon 17 2153A>G Asn718Ser rs3740072 Exon 19 2546T>G Leu849Arg rs17222617 Exon 20 2677G>C Glu893Gln rs3740071 2901C>A Tyr967stop rs17222547 2934G>A synonymous rs3740070 Exon 22 2944A>G Ile982Val rs17222554 3107T>C Ile1036Thr rs17216149Exon 23 3188A>G Asn1063Ser rs17222540 Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 Exon 25 3563T>A Val1188Glu rs17222723 Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 Exon 28 3972C>T synonymous rs3740066 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 4410G>A synonymous rs8187706Exon 31 4488C>T synonymous rs8187707 4527C>T synonymous rs8187709Exon 32 4544G>A Cys1515Tyr rs8187710 ABCG2 PA317 mRNA (n.s.) Protein (n.s.) Drug sensitivity (n.s.) Topotecan uptake (n.s.) Imai et al. [85] mRNA (n.s.) Protein (n.s.) Apical localization (impaired) Drug sensitivity ( ) Indolocarbazole uptake ( ) Indolocarbazole efflux ( ) Mizuarai et al. [88] Exon 2 34G>A Val12Met rs2231137 LLC-PK1 Apical localization (n.s.) . Login to comment 85 ABCG2 p.Gln141Lys ABCG2 p.Ile206Leu ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser ABCG2 p.Ser248Pro ABCG2 p.Phe571Ile ABCG2 p.Ile206Thr ABCG2 p.Ile206Ser ABCG2 p.Ile206Asn Exon Polymorphism Effect dbSNP Cell Expression Function Reference mRNA ( ) Protein (n.s.) Membrane localization (n.s.) Drug sensitivity (n.s.) Mitoxantrone efflux (n.s.) Hoechst 33342 efflux (n.s.) Morisaki et al. [92] HEK293 Protein (n.s.) Transport activity (n.s.) Kondo et al. [94] Protein (n.s.) ATPase activity (n.s.) Mizuarai et al. [88] Sf9 Protein ( ) ATPase activity (n.s.) Hoechst 33342 efflux ( ) Morisaki et al. [92] Exon 2 114T>C synonymous rs12721640 Exon 4 369C>T synonymous rs2231139 PA317 mRNA (n.s.) Protein ( ) Drug sensitivity ( ) Intracellular uptake ( ) Imai et al. [85] mRNA (n.s.) Protein (n.s.) Apical localization (n.s.) Drug sensitivity ( ) Indolocarbazole uptake ( ) Indolocarbazole efflux ( ) Mizuarai et al. [88] LLC-PK1 Apical localization (n.s.) Kondo et al. [94] mRNA ( ) Protein (n.s.) Membrane localization (impaired) Drug sensitivity ( ) Mitoxantrone efflux ( ) Hoechst 33342 efflux (n.s.) Morisaki et al. [92] HEK293 Protein ( ) Transport activity (n.s.) Kondo et al. [94] Protein (n.s.) ATPase activity ( ) Mizuarai et al. [88] 421C>A Gln141Lys rs2231142 Sf9 Protein (n.s.) ATPase activity ( ) Hoechst 33342 efflux (n.s.) Morisaki et al. [92] LLC-PK1 Apical localization (n.s.) Exon 5 496C>G Gln166Glu rs1061017 HEK293 Protein (n.s.) Transport activity (n.s.) Kondo et al. [94] 564A>G synonymous rs3116439 616A>C Ile206Leu rs12721643 HEK293 Protein ( or n.s.) Membrane localization (n.s.) Efflux activity ( ) Drug sensitivity ( ) ATPase activity (n.s.) Vethanayagam et al. [95] 617T>G Ile206Ser 617T>C Ile206Thr 617T>A Ile206Asn rs28365037 Exon 6 623T>C Phe208Ser rs1061018 Exon 7 742T>C Ser248Pro rs3116448 Exon 9 1000G>T Glu334stop rs3201997 Exon 14 2204T>A Phe571Ile rs9282571 SLC15A1 CHO Cephalexin uptake (n.s.)61G>A Val21Ile rs8187818 Cos7 Cephalexin uptake (n.s.) Substrate selectivity (n.s.) CHO Cephalexin uptake ( ) Cos7 Cephalexin uptake ( ) Substrate selectivity (VAC inhibition?) Login to comment 92 ABCC2 p.Val417Ile ABCC2 p.Arg353His ABCC2 p.Asn718Ser ABCC2 p.Leu849Arg ABCC2 p.Asp333Gly ABCC2 p.Ile1036Thr ABCC2 p.Ile670Thr ABCC2 p.Thr486Ile ABCC2 p.Glu893Gln ABCC2 p.Lys495Glu ABCC2 p.Met246Leu ABCC2 p.Asn1063Ser ABCC2 p.Ile982Val ABCC2 p.Phe562Leu Exon Polymorphism Effect dbSNP Subject Expression Function Reference DNT patient Tumoral protein (GG GA) Peritumoral protein (GG GA) Vogelgesang et al. [54] Nasopharyngeal cancer patient Irinotecan PK (CC CT TT) SN-38 PK (CC CT TT) SN-38G PK (CC CT TT) Zhou et al. [56] Colorectal cancer patient (Japanese) Tumoral mRNA (CC CT TT) Drug sensitivity (CC CT TT) Tumor growth rate (CC CT TT) Nishioka et al. [57] HIV patient (Caucasian) Nelfinavir intracellular AUC (CC CT TT) Colombo et al. [58] Spina Bifida patient Disease-susceptibility (CC CT TT) Jensen et al. [60] Cancer patient (Caucasian) Diflomotecan PK (CC CA) Sparreboom et al. [96] 116A>T Tyr2Phe rs927344Exon 2 159A>G synonymous rs17222596 Exon 7 736A>C Met246Leu rs17222744 Exon 8 998A>G Asp333Gly rs17222674 Exon 9 1058G>A Arg353His rs7080681 1219C>T synonymous rs17216198 1249G>A Val417Ile rs2273697 Healthy (Finnish) Pravastatin PK (GG GA AA) Niemi et al. [48] Women undergoing cesarean section Placental mRNA [preterms] (GG>GA>AA), [term] (GG GA AA) Placental protein (GG GA AA) Meyer zu Schwabedissen et al. [52] DNT patient Tumoral protein (GG<GA) Peritumoral protein (GG GA) Vogelgesang et al. [54] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA AA) Colombo et al. [58] Cancer patient (Caucasian) Diflomotecan PK (CC CA) Sparreboom et al. [96] 1434G>T synonymous 1434G>A synonymous rs4267009 Exon 10 1457C>T Thr486Ile rs17222589 Exon 11 1483A>G Lys495Glu rs17222561 Exon 13 1686T>G Phe562Leu rs17216233 2009T>C Ile670Thr rs17222632Exon 16 2073C>A synonymous rs17222624 Exon 17 2153A>G Asn718Ser rs3740072 Exon 19 2546T>G Leu849Arg rs17222617 Exon 20 2677G>C Glu893Gln rs3740071 2901C>A Tyr967stop rs17222547 2934G>A synonymous rs3740070 Exon 22 2944A>G Ile982Val rs17222554 3107T>C Ile1036Thr rs17216149Exon 23 3188A>G Asn1063Ser rs17222540 (Table 3) contd…. Login to comment 93 ABCG2 p.Val12Met ABCC2 p.Lys1299Gln ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu ABCC2 p.Arg1181Leu ABCC2 p.Pro1291Leu Exon Polymorphism Effect dbSNP Subject Expression Function Reference Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 3563T>A Val1188Glu rs17222723 Healthy (Finnish) Pravastatin PK (TT TA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (TT TA) Colombo et al. [58] Exon 25 Patient Acute anthracycline-induced cardiotoxicity (TT<TA) Chronic anthracycline-induced cardiotoxicity (TT TA) Wojnowski et al. [59] Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 3972C>T synonymous rs3740066 Women undergoing cesarean section Placental mRNA (GG GA AA) Placental protein (GG GA AA) Meyer zu Schwabedissen et al. [52] DNT patient Tumoral protein (GG GA) Peritumoral protein (GG GA) Vogelgesang et al. [54] Patient 9-nitrocamptotecin PK and toxicity (CC CT TT) 9-aminocamptotecin PK and toxicity (CC CT TT) Zamboni et al. [55] Exon 28 Colorectal cancer patient (Japanese) Tumoral mRNA (CC CT TT) Drug sensitivity (CC CT TT) Tumor growth rate (CC CT TT) Nishioka et al. [57] 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 Exon 31 4410G>A synonymous rs8187706 4488C>T synonymous rs8187707 HIV patient (Caucasian) Nelfinavir intracellular AUC (CC CT) Colombo et al. [58] 4527C>T synonymous rs8187709 4544G>A Cys1515Tyr rs8187710 Healthy (Finnish) Pravastatin PK (GG GA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 32 Patient Acute anthracycline-induced cardiotoxicity (GG<GA) Chronic anthracycline-induced cardiotoxicity (GG GA) Wojnowski et al. [59] ABCG2 34G>A Val12Met rs2231137 Nasopharyngeal cancer patient Irinotecan PK (GG GA+AA) SN-38 PK (GG GA+AA) SN-38G PK (GG GA+AA) Zhou et al. [56] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 2 Patient (Japanese) Placental mRNA (GG GA AA) Placental protein (GG GA AA) Kobayashi et al. [91] (Table 3) contd…. Login to comment 94 ABCG2 p.Gln141Lys ABCG2 p.Ile206Leu ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser ABCG2 p.Ser248Pro ABCG2 p.Phe571Ile ABCG2 p.Ile206Thr ABCG2 p.Ile206Ser ABCG2 p.Ile206Asn Exon Polymorphism Effect dbSNP Subject Expression Function Reference 114T>C synonymous rs12721640 369C>T synonymous rs2231139 421C>A Gln141Lys rs2231142 Patient (Caucasian) 9-nitrocamptotecin PK (CC CA) 9-aminocamptotecin PK [AUC/Dose] (CC<CA) Zamboni et al. [55] Nasopharyngeal cancer patient Irinotecan PK (CC CA+AA) SN-38 PK (CC CA+AA) SN-38G PK (CC CA+AA) Zhou et al. [56] HIV patient (Caucasian) Nelfinavir intracellular AUC (CC CA AA) Colombo et al. [58] Cancer patient Irinotecan PK (CC CA+AA) SN-38 PK (CC CA+AA) SN-38G PK (CC CA+AA) de Jong et al. [90] Patient (Japanese) Placental mRNA (CC CA AA) Placental protein (CC>CA>AA) Kobayashi et al. [91] Cancer patient Diflomotecan PK [AUC, Cmax] (CC<CA), [F] (CC>CA) Sparreboom et al. [96] Healthy (Chinese) Rosuvastatin PK [AUC, Cmax] (CC<CA+AA), [CL/F] (CC>CA+AA), [T1/2, Tmax] (CC CA+AA) Zhang et al. [97] Exon 4 496C>G Gln166Glu rs1061017 564A>G synonymous rs3116439 616A>C Ile206Leu rs12721643 617T>G Ile206Ser 617T>C Ile206Thr 617T>A Ile206Asn rs28365037 Exon 6 623T>C Phe208Ser rs1061018 Exon 7 742T>C Ser248Pro rs3116448 Exon 9 1000G>T Glu334Stop rs3201997 Exon 14 1711T>A Phe571Ile rs9282571 SLC15A1 61G>A Val21Ile rs8187818Exon 3 83T>A Phe28Tyr rs8187817 258G>A synonymous rs8187823 330C>T synonymous rs8187822 350G>A Ser117Asn rs2297322 351C>A Ser117Arg rs8187821 Exon 5 364G>A Val122Met rs8187820 Exon 7 501C>T synonymous rs3737087 Exon 11 843G>A synonymous r8187812 Exon 15 1147G>A Asp383Asn rs1782674 1179C>T synonymous rs8187836Exon 16 1256G>C Gly419Ara rs4646227 1347T>C synonymous rs1339067 Allelic mRNA imbalance (2030%) Anderle et al. [101] 1348G>A Val450Ile rs2274828 1352C>A Thr451Asn rs8187838 Exon 17 1375C>T Arg459Cys rs2274827 Exon 18 1446A>G synonymous rs8187828 (Table 3) contd…. Login to comment 97 ABCG2 p.Gln141Lys PK: pharmacokinetics DNT: dysembryoplastic neuroepithelial tumors SN-38, SN-38G: irinotecan metabolites HIV: human Immunodeficiency Virus AUC: area under time-drug concentration curve Cmax: maximum drug concentration F: bioavailability CL/F: oral clearance T1/2: blood elimination half-life Tmax: time to peak concetration pendent groups, Mizuarai et al. [88] and Morisaki et al. [92], have shown comparable ABCG2 protein expression in wild-type and variant Gln141Lys transfectants in an immunostaining analysis using LLC-PK1 cells and immunoblot analysis using HEK-293 cells, respectively. Login to comment 99 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met In the report of Mizuarai et al., Val12Met but not Gln141Lys affected apical membrane localization of ABCG2 in transfectant- LLC-PK1 cells, whereas Morisaki et al. reported impaired membrane trafficking or incorrect membrane insertion of Gln141Lys ABCG2 in HEK-293 cells. Login to comment 100 ABCG2 p.Gln141Lys Both groups also demonstrated that variant Gln141Lys ABCG2-expressing cells exhibited altered ATPase activity in Sf9 insect cells with ABCG2-bearing baculovirus and reduced drug resistance to ABCG2 substrates such as mitoxantrone, topotecan, and an indolocarbazole topoisomerase I inhibitor in LLC-PK1 cells or HEK293 cells [88, 92]. Login to comment 101 ABCG2 p.Val12Met ABCG2 p.Val12Met Reduced drug resistance to ABCG2 substrates was also observed in Val12Met ABCG2-transfected LLC-PK1 cells, but not significantly in Val12Met ABCG2-transfected HEK-293 cells. Login to comment 103 ABCG2 p.Ile206Leu On the other hand, the Ile206Leu variant, induced by 616A>C SNP, which occurred at lower allele frequency, exhibited approximately 2-fold wild-type efflux activity in HEK293 cells, whereas its ATPase activities were not significantly different from wild-type protein [95]. Login to comment