ArticlePharmacogenetics and genomics2011
Functional analysis of nonsynonymous single nucleotide polymorphisms of multidrug resistance-associated protein 2 (ABCC2).
Article in Pharmacogenetics and genomics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 34 citations in OpenAlex.
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- Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma.Cancers · 2020Article
- A recurrent ABCC2 p.G693R mutation resulting in loss of function of MRP2 and hyperbilirubinemia in Dubin-Johnson syndrome in China.Orphanet journal of rare diseases · 2020Article
- Pharmacogenetics of Statin-Induced Myotoxicity.Frontiers in genetics · 2020Review
- In vitro Transport Ability ofOncoTargets and therapy · 2020Article
- Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients.Oncotarget · 2018Article
- In Vitro Transport Activity and Trafficking of MRP2/ABCC2 Polymorphic Variants.Pharmaceutical research · 2017Article
- Clinical Perspectives on Targeting Therapies for Personalized Medicine.Advances in protein chemistry and structural biology · 2016Review
- Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples.International journal of cancer research and molecular mechanisms · 2015Article
- Single nucleotide polymorphisms in microRNA binding sites of oncogenes: implications in cancer and pharmacogenomics.Omics : a journal of integrative biology · 2014Article
- Single nucleotide polymorphisms in microRNA binding sites: implications in colorectal cancer.TheScientificWorldJournal · 2014Article
- Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy.The pharmacogenomics journal · 2013Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundMultidrug resistance-associated protein 2 (MRP2; ABCC2) mediates the biliary excretion of glutathione, glucuronide, and sulfate conjugates of endobiotics and xenobiotics. Single nucleotide polymorphisms (SNPs) of MRP2 contribute to interindividual variability in drug disposition and ultimately in drug response.
objectivesTo characterize the transport function of human wild-type (WT) MRP2 and four SNP variants, S789F, A1450T, V417I, and T1477M.
methodsThe four SNP variants were expressed in Sf9 cells using recombinant baculovirus infection. The kinetic parameters [Km, (μmol/l); V(max), (pmol/mg/min); the Hill coefficient] of ATP-dependent transport of leukotriene C(4) (LTC(4)), estradiol-3-glucuronide (E(2)3G), estradiol-17β-glucuronide (E(2)17G), and tauroursodeoxycholic acid (TUDC) were determined in Sf9-derived plasma membrane vesicles. Transport activity was normalized for expression level.
resultsThe V(max) for transport activity was decreased for all substrates for S789F, and for all substrates except E(2)17G for A1450T. V417I showed decreased apparent affinity for LTC(4), E(2)3G, and E(2)17G, whereas transport was similar between wild-type (WT) and T1477M, except for a modest increase in TUDC transport. Examination of substrate-stimulated MRP2-dependent ATPase activity of S789F and A1450T, SNPs located in MRP2 nucleotide-binding domains (NBDs), demonstrated significantly decreased ATPase activity and only modestly decreased affinity for ATP compared with WT.
conclusionSNPs in the NBDs (S789F in the D-loop of NBD1, or A1450T near the ABC signature motif of NBD2) variably decreased the transport of all substrates. V417I in membrane spanning domain 1 selectively decreased the apparent affinity for the glutathione and glucuronide conjugated substrates, whereas the T1477M SNP in the carboxyl terminus altered only TUDC transport.
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