Pharmacogenetics meets metabolomics: Discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition

Im Sook Song, Do Yup Lee, Min Hye Shin, Hyunmi Kim, Yun Gyong Ahn, Inmyoung Park, Kyoung Heon Kim, Tobias Kind, Jae Gook Shin, Oliver Fiehn, Kwang Hyeon Liu

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Clrenal, Clsec, Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2.

Original languageEnglish
Article numbere36637
JournalPLoS One
Volume7
Issue number5
DOIs
Publication statusPublished - 2012 May 8

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pharmacogenomics
metformin
Metabolomics
Metformin
Pharmacogenetics
metabolomics
Tryptophan
tryptophan
transporters
Cations
cations
Substrates
Metabolites
Polymorphism
metabolites
uptake mechanisms
Association reactions
genetic polymorphism
Pharmacokinetics
Metabolome

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pharmacogenetics meets metabolomics : Discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition. / Song, Im Sook; Lee, Do Yup; Shin, Min Hye; Kim, Hyunmi; Ahn, Yun Gyong; Park, Inmyoung; Kim, Kyoung Heon; Kind, Tobias; Shin, Jae Gook; Fiehn, Oliver; Liu, Kwang Hyeon.

In: PLoS One, Vol. 7, No. 5, e36637, 08.05.2012.

Research output: Contribution to journalArticle

Song, IS, Lee, DY, Shin, MH, Kim, H, Ahn, YG, Park, I, Kim, KH, Kind, T, Shin, JG, Fiehn, O & Liu, KH 2012, 'Pharmacogenetics meets metabolomics: Discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition', PLoS One, vol. 7, no. 5, e36637. https://doi.org/10.1371/journal.pone.0036637
Song, Im Sook ; Lee, Do Yup ; Shin, Min Hye ; Kim, Hyunmi ; Ahn, Yun Gyong ; Park, Inmyoung ; Kim, Kyoung Heon ; Kind, Tobias ; Shin, Jae Gook ; Fiehn, Oliver ; Liu, Kwang Hyeon. / Pharmacogenetics meets metabolomics : Discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition. In: PLoS One. 2012 ; Vol. 7, No. 5.
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