Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin.
Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large inter-patient variability in the clinical efficacy of metformin. The sequences of the 5'-flanking and coding regions of the two genes of interest were screened by single-strand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, -43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% (P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin.
Shikata
Eriko
E
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Yamamoto
Rei
R
Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Yonago, Japan.
Takane
Hiroshi
H
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Shigemasa
Chiaki
C
Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Yonago, Japan.
Ikeda
Tadasu
T
Department of Adult and Elderly Nursing, Faculty of Medicine, Tottori University, Yonago, Japan.
Otsubo
Kenji
K
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Ieiri
Ichiro
I
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan. ieiri-ttr@umin.ac.jp.|Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ieiri-ttr@umin.ac.jp.
D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000378:metabolism
D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C491013:SLC22A2 protein, human; D008687:Metformin