title: Pharmacogenetics meets metabolomics: discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition.
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 (Cl(renal), Cl(sec), 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.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Do Yup
authors.initials: DY
authors.lastname: Lee
authors.forename: Min-Hye
authors.initials: MH
authors.lastname: Shin
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Yun Gyong
authors.initials: YG
authors.lastname: Ahn
authors.forename: Inmyoung
authors.initials: I
authors.lastname: Park
authors.forename: Kyoung Heon
authors.initials: KH
authors.lastname: Kim
authors.forename: Tobias
authors.initials: T
authors.lastname: Kind
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D055432:Metabolomics; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D011110:Polymorphism, Genetic; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D014364:Tryptophan; D008687:Metformin