ABCC5 p.Gly1249Ala
| Predicted by SNAP2: | A: D (80%), C: D (85%), D: D (91%), E: D (91%), F: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (85%), P: D (95%), Q: D (91%), R: D (91%), S: D (85%), T: D (91%), V: D (91%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: 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] Metabolism and transport of oxazaphosphorines and ... Drug Metab Rev. 2005;37(4):611-703. Zhang J, Tian Q, Yung Chan S, Chuen Li S, Zhou S, Duan W, Zhu YZ
Metabolism and transport of oxazaphosphorines and the clinical implications.
Drug Metab Rev. 2005;37(4):611-703., [PMID:16393888]
Abstract [show]
The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to bone marrow transplantation for aplastic anemia, leukemia, and other malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), NSC 612567 (aldophosphamide perhydrothiazine), and NSC 613060 (aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used alkylating agents) and the clinical implications. Both CPA and IFO are prodrugs that require activation by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic nitrogen mustards capable of reacting with DNA molecules to form crosslinks and lead to cell apoptosis and/or necrosis. Such prodrug activation can be enhanced within tumor cells by the CYP-based gene directed-enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as glufosfamide, NSC 612567 and NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both NSC 612567 and NSC 613060 can be activated by plain phosphodiesterase (PDEs) in plasma and other tissues or by the high-affinity nuclear 3'-5' exonucleases associated with DNA polymerases, such as DNA polymerases and epsilon. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde (CAA). Various aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated proteins (MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in cancer chemotherapy.
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637 These mainly included C-24T (promoter), G1249A (exon 10), G2026C (exon 16), T2125C (exon 17), C2302T (exon 18), C2366 (exon 18), A3517T (exon 25), G3449 (exon 25), C3972T (exon 28), and G4348A (exon 31).
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ABCC5 p.Gly1249Ala 16393888:637:40
status: NEW[hide] Multidrug resistance associated proteins as determ... Curr Drug Metab. 2007 Dec;8(8):787-802. Yu XQ, Xue CC, Wang G, Zhou SF
Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs.
Curr Drug Metab. 2007 Dec;8(8):787-802., [PMID:18220559]
Abstract [show]
The multidrug resistance associated proteins (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters. They are expressed differentially in the liver, kidney, intestine, brain and other tissues. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. Several MRPs (mainly MRP1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. MRPs transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. Most MRPs are subject to induction and inhibition by a variety of compounds. Several nuclear receptors, including pregnane X receptor (PXR), liver X receptor (LXR), and farnesoid receptor (FXR) participate in the regulation of MRPs. MRPs play an important role in the absorption, distribution and elimination of various drugs in the body and thus may affect their efficacy and toxicity and cause drug-drug interactions. MRPs located in the blood-brain barrier can restrict the penetration of compounds into the central nervous system. Mutation of MRP2 causes Dubin-Johnson syndrome, while mutations in MRP6 are responsible for pseudoxanthoma elasticum. More recently, mutations in mouse Mrp6/Abcc6 gene is associated with dystrophic cardiac calcification (DCC), a disease characterized by hydroxyapatite deposition in necrotic myocytes. A single nucleotide polymorphism, 538G>A in the MRP8/ABCC11 gene, is responsible for determination of earwax type. A better understanding of the function and regulating mechanism of MRPs can help minimize and avoid drug toxicity, unfavourable drug-drug interactions, and to overcome drug resistance.
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405 Important Single Nucleotide Polymorphisms (SNPs) of MRP Genes MRP Chromosomal location Amino acid variation Nucleotide variation Location References Cys43Ser Thr73Ile G128C C218T Exon2 Exon2 [239] Arg433Ser G1299T Exon10 [258] Gly671Val G2012T Exon16 [259] Arg723Gln G2168A Exon17 [239] MRP1 16p13.11-p13.12 Arg1058Gln G3173A Exon23 [239] C-24T Promoter [100, 239] Val417Ile G1249A Exon10 [100, 238, 239] Gly676Arg G2026C Exon16 [237] Try709Arg T2125C Exon17 [236] Arg768Trp Ser789Phe C2302T C2366T Exon18 Exon18 [100, 238, 239] I1173F R1150H A3517T G3449A Exon25 Exon25 [240] Ile1324Ile C3972T Exon28 [100, 239] MRP2 10q23-24 Ala1450Thr G4348A Exon31 [100, 238, 239] (Table 2) contd….
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ABCC5 p.Gly1249Ala 18220559:405:375
status: NEW355 These include C-24T (promoter), G1249A (exon 10), G2026C (exon 16), T2125C (exon 17), C2302T (exon 18), C2366 (exon 18), A3517T (exon 25), G3449 (exon 25), C3972T (exon 28) and G4348A (Exon 31).
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ABCC5 p.Gly1249Ala 18220559:355:32
status: NEW[hide] Pharmacogenetics of irinotecan. Curr Med Chem Anticancer Agents. 2003 May;3(3):225-37. Toffoli G, Cecchin E, Corona G, Boiocchi M
Pharmacogenetics of irinotecan.
Curr Med Chem Anticancer Agents. 2003 May;3(3):225-37., [PMID:12769780]
Abstract [show]
Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
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244 Two of them, one (C24T) located in the promoter of the gene, and one (G1249A) on exon 10, showed a considerable allelic frequency (12.326.1%, and 18.3-31.2%, respectively depending on the Jewish ethnic group) [9] but their effect on MRP2 activity is still unknown.
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ABCC5 p.Gly1249Ala 12769780:244:70
status: NEW[hide] Pharmacogenetics of HIV therapy. Pharmacogenet Genomics. 2006 Oct;16(10):693-703. Owen A, Pirmohamed M, Khoo SH, Back DJ
Pharmacogenetics of HIV therapy.
Pharmacogenet Genomics. 2006 Oct;16(10):693-703., [PMID:17001288]
Abstract [show]
Drug treatment in HIV disease is characterized by variable responses, in terms of both efficacy and toxicity. Both genetic and environmental factors are important determinants of this variability, although the relative contributions are unclear and likely to vary with different drugs. Many of the antiretrovirals are metabolized by polymorphically expressed enzymes (cytochrome P450, CYP450; glucuronyl transferase, GT) and/or transported by drug transporters (ABC and SLC families). Initial studies of antiretroviral efficacy have therefore focused on these genes. For example, it has recently been shown that a CYP2B6 genetic variant predicts higher plasma efavirenz exposure and possibly increased central nervous system toxicity. A large number of studies on ABCB1 genetics with antiretrovirals have also been undertaken; however, as in other therapeutic areas, the data have been contradictory, and currently, no firm conclusions can be reached on the effect of ABCB1 variability as a determinant of efficacy. Indeed, this highlights the need for validation of initial association studies in pharmacogenetic research. By contrast, the clearest association between genetic variants and response relates to the hypersensitivity reaction that occurs with abacavir. The identification that the major histocompatibility complex haplotype 57.1 acts as a strong genetic predisposing factor can be regarded as a prime example of how fundamental research can be translated into a pharmacogenetic test. Nevirapine hypersensitivity has also been related to an HLA gene (HLA-DRB1*0101) but the predictive value does not appear to be sufficient to implement in clinical practice. Much more work needs to be done to define the genetic factors determining response to antiretroviral agents. These studies need to be sufficiently powered and utilize a modern genotyping strategy. Most importantly, the phenotype needs to be carefully characterized. We also need to disseminate this information: a pivotal resource for this can be found at www.HIV-pharmacogenomics.org.
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106 Recently, the pharmacogenetics of ABCC2 (C - 24T and G1249A), ABCC4 (C1612T, A3463G, G3724A and T4131G) ABCG2 (G34A and C421A) and CYP3A5 were assessed in the context of zidovudine and lamivudine triphosphate concentrations [44].
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ABCC5 p.Gly1249Ala 17001288:106:53
status: NEW[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]
Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.
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7118 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1↔ Intracellular C218T T73I 1↔ Normal C257T S92F 2↔ Normal C350T T117M 2↔ Normal G689A R230Q ↔ Normal G1057A V353M N.D. N.D. G1299T R433S 2↔ Normal G1898A R633Q 2↔ Normal G2012T G671V ↔ Normal G2168A R723Q 2 Normal G2965A A989T 2↔ Normal G3140C C1047S 1↔ Normal G3173A R1058Q ↔ Normal C4535T S1512L ↔ Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I ↔ Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T ↔ Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D ↔ Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L ↔ Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G ↔ Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R ↔ Normal C4141A R1381S ↔ Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2↔ Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E ↔ Normal G912T K304N ↔ Normal C1067T T356M N.D. N.D. C1208T P403L 2↔ Normal G1460A G487E 2 Normal A1492G K498E ↔ Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V ↔ Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1↔ Normal G3211A V1071I ↔ Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined.
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ABCC5 p.Gly1249Ala 20103563:7118:550
status: NEW7115 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1 Intracellular C218T T73I 1 Normal C257T S92F 2 Normal C350T T117M 2 Normal G689A R230Q Normal G1057A V353M N.D. N.D. G1299T R433S 2 Normal G1898A R633Q 2 Normal G2012T G671V Normal G2168A R723Q 2 Normal G2965A A989T 2 Normal G3140C C1047S 1 Normal G3173A R1058Q Normal C4535T S1512L Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R Normal C4141A R1381S Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2 Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E Normal G912T K304N Normal C1067T T356M N.D. N.D. C1208T P403L 2 Normal G1460A G487E 2 Normal A1492G K498E Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1 Normal G3211A V1071I Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; , no change in function; N.D. not determined.
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ABCC5 p.Gly1249Ala 20103563:7115:538
status: NEW[hide] Variable expression of MRP2 (ABCC2) in human place... Drug Metab Dispos. 2005 Jul;33(7):896-904. Epub 2005 Apr 8. Meyer zu Schwabedissen HE, Jedlitschky G, Gratz M, Haenisch S, Linnemann K, Fusch C, Cascorbi I, Kroemer HK
Variable expression of MRP2 (ABCC2) in human placenta: influence of gestational age and cellular differentiation.
Drug Metab Dispos. 2005 Jul;33(7):896-904. Epub 2005 Apr 8., [PMID:15821043]
Abstract [show]
MRP2 (ABCC2) is an ATP-binding cassette (ABC)-type membrane protein involved in transport of conjugates of various drugs and endogenous compounds. MRP2 has been localized to the apical membrane of syncytiotrophoblasts and is assumed to be involved in diaplacental transfer of the above substances. It has been shown that both genetic and environmental factors can influence MRP2 expression. We therefore investigated whether gestational age, cellular differentiation, and genetic polymorphisms influence expression and localization of MRP2 in 58 human placenta samples. We detected a significant increase of transporter-mRNA with gestational age by quantitative real-time polymerase chain reaction (MRP2 mRNA/18S rRNA ratio x 1000 +/- S.D.; 0.43 +/- 0.13 in early preterms versus 1.18 +/- 0.44 in late preterms versus 2.1 +/- 0.63 in terms; p < 0.05). MRP2 protein followed the mRNA amount as shown by Western blotting (mean relative band intensity +/- S.D.; 0.56 +/- 0.1 versus 0.7 +/- 0.18 versus 0.92 +/- 0.19; early preterms versus terms p < 0.05). In cultured cytotrophoblasts, MRP2 expression increased with differentiation to syncytiotrophoblasts, with a peak on day 2 (MRP2 mRNA/18S rRNA ratio x 1000 +/- S.D.; 0.06 +/- 0.01 versus 0.88 +/- 0.27 versus 0.24 +/- 0.02 on days 0, 2, and 4). Moreover, we studied the effect of single nucleotide polymorphisms (C-24T; G1249A, and C3972T) in the MRP2 gene on placental expression. One of these polymorphisms (G1249A) resulted in a significantly reduced expression of MRP2 mRNA in preterms. In summary, the expression of MRP2 in human placenta is influenced by gestational age, cellular differentiation, and genetic factors.
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35 In this paper we demonstrate a significant reduced expression in preterm placenta, increased expression during in vitro differentiation, and an influence of the G1249A polymorphism.
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ABCC5 p.Gly1249Ala 15821043:35:161
status: NEW120 These primers were used for amplification of a 301-bp fragment in the 5Ј-flanking region containing the C-24T variant of a 260-bp fragment in exon 10 containing the G1249A variant, and of a 184-bp fragment in exon 28 containing the 3972 polymorphism.
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ABCC5 p.Gly1249Ala 15821043:120:171
status: NEW186 Moreover, 5 homozygotes and 16 heterozygotes of the missense mutation G1249A (exon 10) were identified.
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ABCC5 p.Gly1249Ala 15821043:186:70
status: NEW215 Protein expression of MRP2, which has been established in a subset of the placental samples, did not differ in relation to the G1249A genotype [mean relative band intensity Ϯ S.D.; terms: 1249 GG, 0.77 Ϯ 0.28 (n ϭ 6), and terms: 1249 GA, 1.00 Ϯ 0.30 (n ϭ 7); Kruskal-Wallis test: 2 ϭ 1.479; df ϭ 1; p ϭ 0.224].
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ABCC5 p.Gly1249Ala 15821043:215:127
status: NEW[hide] Polymorphism in multidrug resistance-associated pr... Pharmacogenomics J. 2012 Oct;12(5):386-94. doi: 10.1038/tpj.2011.17. Epub 2011 May 24. Ansari M, Sauty G, Labuda M, Gagne V, Rousseau J, Moghrabi A, Laverdiere C, Sinnett D, Krajinovic M
Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia.
Pharmacogenomics J. 2012 Oct;12(5):386-94. doi: 10.1038/tpj.2011.17. Epub 2011 May 24., [PMID:21606946]
Abstract [show]
Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were investigated for an association with treatment responses in 273 childhood ALL patients. The MRP3 A-189 allele of the regulatory AT polymorphism was associated with reduced event-free survival (P=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A-189 carriers had significantly higher methotrexate plasma levels (P=0.03). MRP3 A-189 also conferred four times higher risk of a relapse in central nervous system (P=0.01). Patients with this allele tended to have lower frequency of thrombocytopenia grade 2 (P=0.06). Gene reporter assay showed that the haplotype tagged by the A-189 had higher promoter activity (P</=0.01). In conclusion, MRP3 A-189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux.
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131 Several polymorphisms have been widely studied in MRP2 gene including 50 UTR C-24 T substitution and non-synonymous G1249A, T3563A and G4544A variations leading to Val417Ile, Val1188Glu and Cys1515Tyr amino-acid replacements, respectively.
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ABCC5 p.Gly1249Ala 21606946:131:116
status: NEW