ABCB1 p.Cys431Leu
| Predicted by SNAP2: | A: N (53%), D: D (91%), E: D (91%), F: D (85%), G: D (80%), H: D (91%), I: D (85%), K: D (91%), L: D (85%), M: D (59%), N: D (85%), P: D (91%), Q: D (91%), R: D (91%), S: N (57%), T: D (80%), V: D (80%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] A novel MDR1 GT1292-3TG (Cys431Leu) genetic variat... AAPS J. 2010 Dec;12(4):548-55. Epub 2010 Jul 10. Crouthamel MH, Wu D, Yang Z, Ho RJ
A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions.
AAPS J. 2010 Dec;12(4):548-55. Epub 2010 Jul 10., [PMID:20623213]
Abstract [show]
P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood-brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 (GT1292-3TG) (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 (GT1292-3TG) recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 (GT1292-3TG) recombinant cells exposed exhibited a 75% decrease in IC for doxorubicin (162.6 +/- 17.4 to 37.9 +/- 2.6 nM) and a 50% decrease in IC(50) for paclitaxel (155.7 +/- 27.5 to 87.7 +/- 9.2 nM), vinblastine (128.0 +/- 15.9 to 65.9 +/- 5.1 nM), and vincristine (593.7 +/- 61.8 to 307.3 +/- 17.0 nM). The effects of the Cys431Leu variation, due to MDR1 (GT1292-3TG) 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). Collectively, these data suggest MDR1 (GT1292-3TG) variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype.
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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.
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ABCB1 p.Cys431Leu 20623213:0:42
status: NEW4 We have identified a novel MDR1GT1292-3TG (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia.
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ABCB1 p.Cys431Leu 20623213:4:43
status: NEW8 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).
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ABCB1 p.Cys431Leu 20623213:8:19
status: NEW99 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.
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ABCB1 p.Cys431Leu 20623213:99:221
status: NEW131 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.
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ABCB1 p.Cys431Leu 20623213:131:136
status: NEW135 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.
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ABCB1 p.Cys431Leu 20623213:135:158
status: NEW137 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.
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ABCB1 p.Cys431Leu 20623213:137:96
status: NEW156 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.
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ABCB1 p.Cys431Leu 20623213:156:46
status: NEW159 Our cytotoxicity studies showed that Cys431Leu substitution resulted in a significant increase in sensitivity to chemotherapeutic drugs.
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ABCB1 p.Cys431Leu 20623213:159:37
status: NEW193 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.
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ABCB1 p.Cys431Leu 20623213:193:196
status: NEW211 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.
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ABCB1 p.Cys431Leu 20623213:211:129
status: NEW213 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.
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ABCB1 p.Cys431Leu 20623213:213:24
status: NEW218 It must also be noted that this Cys431Leu variation is the result of two mutations occurring simultaneously at nucleotides 1292 and 1293.
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ABCB1 p.Cys431Leu 20623213:218:32
status: NEW222 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.
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ABCB1 p.Cys431Leu 20623213:222:276
status: NEW223 CONCLUSION We investigated a novel human MDR1GT1292-3TG (Cys431Leu) variation.
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ABCB1 p.Cys431Leu 20623213:223:57
status: NEW226 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.
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ABCB1 p.Cys431Leu 20623213:226:50
status: NEW[hide] Pharmacogenetics of drug transporters in the enter... Pharmacogenomics. 2011 May;12(5):611-31. Stieger B, Meier PJ
Pharmacogenetics of drug transporters in the enterohepatic circulation.
Pharmacogenomics. 2011 May;12(5):611-31., [PMID:21619426]
Abstract [show]
This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.
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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].
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ABCB1 p.Cys431Leu 21619426:91:456
status: NEW712 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.
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ABCB1 p.Cys431Leu 21619426:712:66
status: NEW94 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].
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ABCB1 p.Cys431Leu 21619426:94:457
status: NEW709 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.
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ABCB1 p.Cys431Leu 21619426:709:66
status: NEW[hide] Possible roles of the xenobiotic transporter P-gly... Asian Pac J Cancer Prev. 2013;14(5):3213-7. Ozdemir S, Uludag A, Silan F, Atik SY, Turgut B, Ozdemir O
Possible roles of the xenobiotic transporter P-glycoproteins encoded by the MDR1 3435 C>T gene polymorphism in differentiated thyroid cancers.
Asian Pac J Cancer Prev. 2013;14(5):3213-7., [PMID:23803106]
Abstract [show]
BACKGROUND: P-glycoprotein (Pgp), encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter which plays an important role in pharmacokinetics. The current preliminary study was designed to determine associations between a germ-line polymorphism in the MDR1 gene with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: In the current case-control study, 60 differentiated thyroid cancers (DTC)- 45 papillary TC (PTC), 9 follicular TC(FTC) and 6 well-differentiated tumors of uncertain malignant potential (WDT-UMP) were examined. Results were compared to a healthy control group (n=58) from the same population. Genomic DNA was extracted from peripheral blood with EDTA and the target gene was genotyped by real-time PCR. RESULTS: Carriers of the variant allele of MDR1 exon 26 polymorphism were at 2.8-fold higher risk of DTC than the control group (odds ratio [OR]: 0.3805, 95% confidence interval [Cl]: 0.1597-0.9065 (p> 0.046). CONCLUSIONS: Presented results suggest that the MDR1 3435TT genotype might influence risk of development of DTC and that the CC genotype might be linked to a poor prognosis. Large-scale studies are now needed to validate this association.
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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).
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ABCB1 p.Cys431Leu 23803106:88:63
status: NEW