ABCMdb

ABCB1 p.Cys431Leu

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Publications

PMID: 20623213 [PubMed] Crouthamel MH et al: "A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions."

No. Sentence Comment

0 Research Article A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions Matthew H. Crouthamel,1 Daniel Wu,2 Ziping Yang,1,3 and Rodney J. Y. Ho1,4 Received 11 February 2010; accepted 18 June 2010; published online 10 July 2010 Abstract. Login to comment
4 We have identified a novel MDR1GT1292-3TG (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. Login to comment
8 The effects of the Cys431Leu variation, due to MDR1GT1292-3TG nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p<0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p<0.05). Login to comment
99 Allelic Frequency of MDR1 1292-3 Variants in Leukemia Subjects Sequence/variation Amino acid variation Estimated allelic frequency in leukemia patients Copies per ng RNA Wild type Cys 431 0.9865 459±293 GT 1292-3 TG Cys 431 Leu 0.0135 1126±137* The RNA from 74 leukemia patients was collected, and the MDR1 RNA transcripts were reverse transcribed into complementary DNA. Login to comment
131 White bars rhodamine123, black bars rhodamine123+GF120918 ATPase Activity ATPase activity was measured to determine if the change from cysteine to leucine at amino acid 431 in the nucleotide binding domain (NBD) would alter the ability of P-gp to hydrolyze ATP to ADP. Login to comment
135 Based on our MDR1 sequence variation analysis, we discovered the novel MDR1GT1292-3TG nucleotide variation that translates to an amino acid substitution from cysteine to leucine at position 431. Login to comment
137 In this study, we used MDR1GT1292-3TG recombinant HEK cells that express a P-gp variant, with a Cys to Leu substitution at amino acid 431, to evaluate functional changes. Login to comment
156 Although a direct comparison of Cys431Ala and Cys431Leu with WT P-gp in HEK recombinant cells remained, such a study is beyond the scope of this report. Login to comment
159 Our cytotoxicity studies showed that Cys431Leu substitution resulted in a significant increase in sensitivity to chemotherapeutic drugs. Login to comment
193 The substrate-specific differences in intracellular accumulation do not appear to link with ATPase activity. Our studies of the ATPase activity showed no difference between the wild-type P-gp and Cys431Leu variant. Login to comment
211 In our MDR1GT1292-3TG variant, there are no amino acid changes within the TM segments; the MDR1GT1292-3TG variation results in a Cys431Leu substitution in the ATP binding domain. Login to comment
213 We hypothesize that the Cys431Leu change may affect the communication between the NBD and the TM domains, resulting in altered conformation of the TM segments during ATP binding and/or ATP hydrolysis. Login to comment
218 It must also be noted that this Cys431Leu variation is the result of two mutations occurring simultaneously at nucleotides 1292 and 1293. Login to comment
222 Regardless, if our hypothesis is correct in that the change in P-gp-mediated resistance and uptake is due to the increase in size and hydrophobicity of the resulting amino acid 431 compared with Cys, we believe that the Cys431Phe and Cys431Trp may have similar results to the Cys431Leu transition, and remains to be investigated. Login to comment
223 CONCLUSION We investigated a novel human MDR1GT1292-3TG (Cys431Leu) variation. Login to comment
226 Drug uptake studies showed that the effect of the Cys431Leu variation results in a substrate-specific effect where doxorubicin, vinblastine, and paclitaxel had an increased uptake, while verapamil and Hoechst33342 had a decreased uptake compared with wild type. Login to comment

PMID: 21619426 [PubMed] Stieger B et al: "Pharmacogenetics of drug transporters in the enterohepatic circulation."

No. Sentence Comment

91 Gene name Transporter SNP Protein Population size (n) Invitro function Ref. Intestinal uptake transporters SLC15A1 PEPT1 p.P586L 44 Reduced Vmax [81] p.F28Y 247 Increased Km [82] Intestinal efflux transporters ABCB1 MDR1 c.571G>A p.G191R N/A Reduced drug resistance [201] c.1199G>A p.S440N N/A Reduced activity (substrate dependent) [202] c.11199G>A c.1199G>t p.S440N p.S440I N/A N/A Increased drug resistance Reduced drug resistance [203] c.1292-3GT>TG p.C431L N/A Reduced drug resistance [204] c.2005C>T p.R669C N/A Reduced substrate affinity [202] c.2547A>G p.I849M N/A Increased transport activity [202] c.2677G>T p.A893S 60 Lower intracellular digoxin accumulation [205] c.2677G>T c.2677G>A p.A893S p.A893T N/A N/A Unchanged Unchanged [206] c.2677G>T p.A893S 46 No change in rhodamine 123 efflux from peripheral blood lymphocytes [207] c.2667G>T p.A893S N/A Reduced transport function [208] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased transport function Increased transport function [209] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased activity (substrate dependent) Increased substrate affinity and transportactivity [202] c.2667G>T p.A893S 48 No change in rhodamine 123 efflux activity in peripheral blood mononuclear cells [210] c.2956A>G p.M986V N/A Increased transport activity [202] c.2995G>A p.A999T N/A Increased substrate affinity and transportactivity [202] c.3151C>G p.P1051A N/A Increased transport activity (substratedependent) [202] c.3188G>C p.G1063A N/A Increased transport activity [202] ABCG2 ABCG2 c.34G>A p.V12M N/A Low transport protein expression invitro [211] c.34G>A p.V12M N/A Unchanged [212] c.34G>A p.V12M N/A No change in HEK-293, lowered transport activity in Sf9 cells invitro [213] c.34G>A p.V12M N/A Unchanged [214] c.421C>A p.Q141K N/A Lower transport protein expression, normal transport activity [212] c.421C>A p.Q141K N/A Reduced drug resistance and lower ATPaseactivity [213] c.421C>A p.Q141K N/A Reduced drug extrusion [215] c.421C>A p.Q141K N/A Reduced drug resistance [216] c.421C>A p.Q141K N/A Unchanged [217] c.421C>A p.Q141K N/A No change of intracellular porphyrin accumulation [218] c.421C>A p.Q141K N/A Reduced transport activity [219] c.421C>A p.Q141K N/A Reduced transport activity [55] c.421C>A p.Q141K N/A Increased Km [220] For more information on members of the SLC superfamily of transporters please consult [301] and for more information of ABC transporters please consult [302]. Login to comment
712 204 Crouthamel MH, Wu D, Yang Z, Ho RJ: A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions. Login to comment
94 Gene name Transporter SNP Protein Population size (n) In vitro function Ref. Intestinal uptake transporters SLC15A1 PEPT1 p.P586L 44 Reduced Vmax [81] p.F28Y 247 Increased Km [82] Intestinal efflux transporters ABCB1 MDR1 c.571G>A p.G191R N/A Reduced drug resistance [201] c.1199G>A p.S440N N/A Reduced activity (substrate dependent) [202] c.11199G>A c.1199G>t p.S440N p.S440I N/A N/A Increased drug resistance Reduced drug resistance [203] c.1292-3GT>TG p.C431L N/A Reduced drug resistance [204] c.2005C>T p.R669C N/A Reduced substrate affinity [202] c.2547A>G p.I849M N/A Increased transport activity [202] c.2677G>T p.A893S 60 Lower intracellular digoxin accumulation [205] c.2677G>T c.2677G>A p.A893S p.A893T N/A N/A Unchanged Unchanged [206] c.2677G>T p.A893S 46 No change in rhodamine 123 efflux from peripheral blood lymphocytes [207] c.2667G>T p.A893S N/A Reduced transport function [208] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased transport function Increased transport function [209] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased activity (substrate dependent) Increased substrate affinity and transport activity [202] c.2667G>T p.A893S 48 No change in rhodamine 123 efflux activity in peripheral blood mononuclear cells [210] c.2956A>G p.M986V N/A Increased transport activity [202] c.2995G>A p.A999T N/A Increased substrate affinity and transport activity [202] c.3151C>G p.P1051A N/A Increased transport activity (substrate dependent) [202] c.3188G>C p.G1063A N/A Increased transport activity [202] ABCG2 ABCG2 c.34G>A p.V12M N/A Low transport protein expression in vitro [211] c.34G>A p.V12M N/A Unchanged [212] c.34G>A p.V12M N/A No change in HEK-293, lowered transport activity in Sf9 cells in vitro [213] c.34G>A p.V12M N/A Unchanged [214] c.421C>A p.Q141K N/A Lower transport protein expression, normal transport activity [212] c.421C>A p.Q141K N/A Reduced drug resistance and lower ATPase activity [213] c.421C>A p.Q141K N/A Reduced drug extrusion [215] c.421C>A p.Q141K N/A Reduced drug resistance [216] c.421C>A p.Q141K N/A Unchanged [217] c.421C>A p.Q141K N/A No change of intracellular porphyrin accumulation [218] c.421C>A p.Q141K N/A Reduced transport activity [219] c.421C>A p.Q141K N/A Reduced transport activity [55] c.421C>A p.Q141K N/A Increased Km [220] For more information on members of the SLC superfamily of transporters please consult [301] and for more information of ABC transporters please consult [302]. Login to comment
709 204 Crouthamel MH, Wu D, Yang Z, Ho RJ: A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions. Login to comment

PMID: 23803106 [PubMed] Ozdemir S et al: "Possible roles of the xenobiotic transporter P-glycoproteins encoded by the MDR1 3435 C>T gene polymorphism in differentiated thyroid cancers."

No. Sentence Comment

88 (2010) have reported a novel genetic variation of GT1292-3TG, (Cys431Leu) in MDR1 gene in leukemia patients by the accumulation of the intracellular doxorubicin, vinblastine, and paclitaxel (Crouthamel et al., 2010). Login to comment