Polymorphic variants of MRP4/ABCC4 differentially modulate the transport of methylated arsenic metabolites and physiological organic anions

Banerjee, Minakshi; Marensi, Vanessa; Conseil, Gwenaëlle; Le, X. Chris; Cole, Susan P.C.; Leslie, Elaine M.

doi:10.1016/j.bcp.2016.09.016

Cited by 34 publications

(26 citation statements)

References 57 publications

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“…functional evidence indicates, at least in some cases, that they overlap physically (i.e., they have at least some contact amino acids in common) (15,16,35). Whether or not all of the binding sites or just some of them are bipartite in nature, as is the case for LTC 4 , is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Generation of hMRP1-M1093 single, double, and triple mutants by site-directed mutagenesis hMRP1-M1093 Ala and Leu single mutants were introduced by a 1-step, PCR-based, site-directed mutagenesis using the Quickchange II XL Kit (Agilent Technologies, Santa Clara, CA, USA) and pcDNA3.1(2)-MRP1 as template (24,35) with the following primers (nucleotides changed are underlined): M1093A, 59-GT-CATCAAGGCGTTCATGGGCTCCCTG-39; M1093L, 59-GGT-CATCAAGTTGTTCATGGGCTCCCTG-39 (Integrated DNA Technologies, Coralville, IA, USA). The M1093-W1246A, W553-W1246A, and W553-M1093A double mutants and the triple W553-M1093-W1246A mutant were created using pcDNA3.1(2)-MRP1-M1093A and pcDNA3.1(2)-MRP1-W1246A as templates, and the following primers to introduce the second and third mutations: W553A, 59-GCACCTTCACCGCGGTCTGCACGCC-CTTT-39; W1246A, 59-CGTACTTGAACGCGCTGGTTCGGAT-GTC-39.…”

Section: Generation Of Homology Models Of Hmrp1mentioning

confidence: 99%

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Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

et al. 2019

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The human multidrug resistance protein 1 (hMRP1) transporter is implicated in cancer multidrug resistance as well as immune responses involving its physiologic substrate, glutathione (GSH)‐conjugated leukotriene C4 (LTC4). LTC4 binds a bipartite site on hMRP1, which a recent cryoelectron microscopy structure of LTC4‐bound bovine Mrp1 depicts as composed of a positively charged pocket and a hydrophobic (H) pocket that binds the GSH moiety and surrounds the fatty acid moiety, respectively, of LTC4. Here, we show that single Ala and Leu substitutions of H‐pocket hMRP1‐Met1093 have no effect on LTC4 binding or transport. Estrone 3‐sulfate transport is also unaffected, but both hMRP1‐Met1093 mutations eliminate estradiol glucuronide transport, demonstrating that these steroid conjugates have binding sites distinct from each other and from LTC4. To eliminate LTC4 transport by hMRP1, mutation of 3 H‐pocket residues was required (W553/M1093/W1246A), indicating that H‐pocket amino acids are key to the vastly different affinities of hMRP1 for LTC4 vs. GSH alone. Unlike organic anion transport, hMRP1‐mediated drug resistance was more diminished by Ala than Leu substitution of Met1093. Although our findings generally support a structure in which H‐pocket residues bind the lipid tail of LTC4, their critical and differential role in the transport of conjugated estrogens and anticancer drugs remains unexplained.—Conseil, G., Arama‐Chayoth, M., Tsfadia, Y., Cole, S. P. C. Structure‐guided probing of the leukotriene C4 binding site in human multidrug resistance protein 1 (MRP1; ABCC1). FA8EB J. 33, 10692–10704 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Section: Generation Of Homology Models Of Hmrp1mentioning

confidence: 99%

Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

et al. 2019

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“…Additionally, unlike in the prior report (32) which noted reduced protein expression for the 187W mutant, this mutant was fully expressed in oocytes by Western blot analysis; this discrepancy is perhaps a reflection of the different expression systems utilized (transient transfection of HEK293 cells versus direct microinjection of cRNA in Xenopus oocytes). A recent report, also using transient transfection of HEK293T, cells also reported normal expression of the 187W mutant (35). …”

Section: Resultsmentioning

confidence: 81%

“…ABCC4 is a very polymorphic gene with, for example, >400 missense variants reported in the Exome Aggregation Consortium database of 60,706 unrelated individuals (38), although 1036L is not present in this database. Some of the variants have been evaluated for effect on functional characteristics of MRP4, for example contributing to intracellular accumulation of antiviral agents (32) and methylated arsenic metabolites (35), and to inappropriate lack of localization to the plasma membrane (35). With urate control and risk of gout as clinical outcomes it will be necessary to systematically test missense variants of ABCC4 for association with urate concentrations and risk of gout, and to evaluate their influence on the ability of MRP4 to transport uric acid.…”

Section: Discussionmentioning

confidence: 99%

Population‐Specific Resequencing Associates the ATP‐Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

Tanner

Boocock

Stahl

et al. 2017

Arthritis & Rheumatology

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Objective There is no evidence for genetic association of the organic anion transporters (OAT) 1–3 (SLC22A6, SLC22A7, SLC22A8) and multi-drug resistance protein 4 (MRP4; ABCC4) with serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand (NZ) has the highest prevalence of gout worldwide. Our aim was to determine if there were any Polynesian population-specific genetic variants in the SLC22A6-8 and ABCC4 genes associated with gout. Participants and Methods All participants had ≥3 self-reported Māori and/or Pacific grandparents. From the total sample set of 1808 participants, 191 hyperuricaemic and 202 normouricaemic individuals were resequenced over the four genes with the remaining 1415 individuals used for replication. Regression analyses were performed adjusting by age, sex and Polynesian ancestry. To study the functional effect of non-synonymous variants ABCC4 transport assays were done in Xenopus laevis ooctyes. Results A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. Rs4148500 was monomorphic (for the protective major allele) in Europeans. There was evidence for association for rs4148500 with gout in the resequenced samples (OR=1.62, P=0.012) that was replicated (OR=1.25, P=0.033) and restricted to males (ORMales=1.43, P=0.001; ORFemales=0.98, P=0.89). The gout risk allele was associated with FEUA in males (β=−0.570, P=0.01). A rare population-specific variant (P1036L) with strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%. Conclusion Association of ABCC4 with gout and FEUA is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.

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“…In the human body, MRP4/ABCC4 is mainly responsible for the export of methylated As from hepatocytes to the blood and from renal proximal tubular cells to urine [25]. A recent study expressed multiple MRP4 variants (C171G-, G187W-, K304N-, Y556C-, and wildtype MRP4) in human embryonic kidney cell line and found the As transporting capacities of them were highly variable; these variants were also related to interindividual differences in As susceptibility [55]. …”

Section: Host Genetic Variations Affect As Susceptibilitymentioning

confidence: 99%

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome

Chi

Gao

et al. 2018

Mamm Genome

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Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in inter-individual susceptibility to As-related diseases.

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Polymorphic variants of MRP4/ABCC4 differentially modulate the transport of methylated arsenic metabolites and physiological organic anions

Cited by 34 publications

References 57 publications

Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

Population‐Specific Resequencing Associates the ATP‐Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome

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Polymorphic variants of MRP4/ABCC4 differentially modulate the transport of methylated arsenic metabolites and physiological organic anions

Cited by 34 publications

References 57 publications

Structure‐guided probing of the leukotriene C4binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

Structure‐guided probing of the leukotriene C4binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

Population‐Specific Resequencing Associates the ATP‐Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome

Contact Info

Product

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Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)

Structure‐guided probing of the leukotriene C₄binding site in human multidrug resistance protein 1 (MRP1; ABCC1)