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

• Published in: PloS one Vol. 7; no. 5; p. e36637
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.05.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Antidiabetics; Biological Transport - drug effects; Biological Transport - genetics; Biomarkers; Chemistry; Cloning; Clustering; Discriminant analysis; Enzymes; Female; Genetic aspects; Genetic diversity; Genetic polymorphisms; Genetic variance; Genomes; Genotypes; Heterozygote; Homozygote; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Kidney cancer; Life sciences; Male; Mass spectrometry; Medicine; Metabolism; Metabolites; Metabolomics; Metadata; Metformin; Metformin - administration & dosage; Metformin - pharmacology; Multivariate analysis; Oct-2 protein; Oocytes; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Organic cation transporter; Organic Cation Transporter 2; Pharmacogenetics; Pharmacogenomics; Pharmacology; Physiology; Polymorphism, Genetic; Proteins; Rodents; Scientific imaging; Transport; Tryptophan; Tryptophan - genetics; Tryptophan - metabolism; Uridine; Urine; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036637

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.