Association of multidrug resistance-associated protein 2 single nucleotide polymorphism rs12762549 with the basal plasma levels of phase II metabolites of isoflavonoids in healthy Japanese individuals

• Published in: Pharmacogenetics and genomics Vol. 22; no. 5; pp. 344 - 354
• Main Authors: Kato, Koji, Kusuhara, Hiroyuki, Kumagai, Yuji, Ieiri, Ichiro, Mori, Haruyuki, Ito, Sumito, Nakai, Yasuhiro, Maeda, Kazuya, Sugiyama, Yuichi
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins, Inc 01-05-2012; Lippincott Williams & Wilkins
• Subjects: Adult; Alleles; Animals; Biological and medical sciences; General pharmacology; Genetic Association Studies; Genistein - administration & dosage; Genistein - pharmacokinetics; Humans; Isoflavones - administration & dosage; Isoflavones - pharmacokinetics; Japan; Male; Medical sciences; Metabolic Detoxication, Phase II - genetics; Multidrug Resistance-Associated Proteins - blood; Multidrug Resistance-Associated Proteins - genetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Rats; Rats, Sprague-Dawley; Young Adult; Metabolomics; Plasma; Pharmacogenetics; untargeted metabolomics; multidrug resistance-associated protein 2; Metabolite; Japanese; Protein; Resistance; Association; Single nucleotide polymorphism; isoflavonoids; ATP-binding cassette transporter; ABC transporter
• ISSN: 1744-6872; 1744-6880
• DOI: 10.1097/FPC.0b013e3283517012

OBJECTIVESMultidrug resistance-associated protein 2 (MRP2; ABCC2) is an ATP-binding cassette transporter that mediates the efflux of anionic drugs and phase II metabolites. Our aim was to elucidate the impact of a single nucleotide polymorphism, rs12762549 (G>C), on the in-vivo activity of MRP2.
METHODSPlasma specimens collected from 18 healthy volunteers were subjected to an untargeted metabolomic analysis using liquid chromatography-mass spectrometry. The role of MRP2 in the disposition of substances of interest was then examined in vivo in Mrp2-deficient mutant rats (Eisai hyperbilirubinemic rats; EHBRs) and in vitro in human MRP2-expressing membrane vesicles.
RESULTSA multivariate analysis model using liquid chromatography-mass spectrometry data sets successfully differentiated the GG and the CC genotypes of rs12762549. The C allele is associated with the basal plasma levels of the five phase II metabolites of genistein and dihydrogenistein. Such phase II metabolites were also accumulated in EHBR, compared with normal rats, partly because of the reduced biliary excretion. Following oral administration of genistein and daidzein, the plasma concentrations of total genistein and total daidzein, which were mainly accounted for by sulfoglucuronide conjugates, were markedly higher in EHBR than in normal rats. ATP-dependent uptake of sulfoglucuronides and glucuronides of the isoflavonoids was observed only in MRP2-expressing membrane vesicles.
CONCLUSIONMRP2 plays a significant role in preventing the accumulation of phase II metabolites of isoflavonoids. The rs12762549 is associated with an interindividual difference in the plasma levels of MRP2 substrates, phase II metabolites of isoflavonoids, suggesting that this single nucleotide polymorphism is associated with variations in in-vivo MRP2 activity.