Single nucleotide polymorphisms of ABCC2 modulate renal secretion of endogenous organic anions
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu srovnávací studie, časopisecké články, validační studie
PubMed
28532626
DOI
10.1016/j.bcp.2017.05.012
PII: S0006-2952(17)30279-4
Knihovny.cz E-zdroje
- Klíčová slova
- ABCC2, Endogenous substrates, Metabolomics, Multidrug resistance-associated protein 2, Single nucleotide polymorphisms,
- MeSH
- alely MeSH
- analýza hlavních komponent MeSH
- biologické markery moč MeSH
- biologické modely * MeSH
- diskriminační analýza MeSH
- dospělí MeSH
- eliminace ledvinami * MeSH
- exony MeSH
- frekvence genu MeSH
- genetické asociační studie MeSH
- jednonukleotidový polymorfismus * MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metabolomika metody MeSH
- mladý dospělý MeSH
- organické látky moč MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- validační studie MeSH
- Geografické názvy
- Francie MeSH
- Názvy látek
- ABCC2 protein, human MeSH Prohlížeč
- biologické markery MeSH
- organické látky MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům MeSH
The ATP-binding cassette family transporter MRP2 (multidrug resistance-associated protein 2), encoded by the ABCC2 gene, is involved in the renal excretion of numerous xenobiotics and it is likely that it also transports many endogenous molecules arising from not only normal essential metabolic processes but also from environmental toxins or food intake. We used a targeted gas chromatography-mass spectrometry metabolomics analysis to study whether endogenous organic anions are differentially excreted in urines of healthy volunteers according to their genotype for three functional single nucleotide polymorphisms (SNPs) in ABCC2. This was the case for 35 of the 108 metabolites analyzed. Eight of them are most likely substrates of MRP2 since they are the most contributive to the difference between carriers of a decreasing function allele vs those carrying an increasing function one. Seven out of 8 metabolites are fatty acids (dodecanoic acid; 3-hydroxypropanoic acid) or metabolites of polyphenols (caffeine; resorcinol; caffeic acid; 2-(3,4-dihydroxyphenyl) acetic acid; and 4-hydroxyhippuric acid). Most of them were structurally similar to a series of substances previously shown to interact with MRP2 function in vitro. Interestingly, coproporphyrin isomer I, a prototypical substrate of MRP2, also belonged to our final list although it was not significantly discriminant on its own. This suggests that the simultaneous measurement of a set of endogenous metabolites in urine, rather than that of unique metabolites, has the potential to provide a phenotypic measure of MRP2 function in vivo. This would represent an innovative tool to study the variability of the transport activity of MRP2 under a physiological or pathological condition, especially in pharmacokinetic studies of its substrates.
Centre hospitalier universitaire de Tours Service de néphrologie transplantation Tours France
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