Background and Aim

Organic cation transporters have critical role for absorption, distribution, metabolism, and elimination of many endogenous small organic cations as well as a wide array of drugs. These transporters act as uptake transporters (OCT1, OCT2, OCT3 and PMAT) or efflux transporters (MATE1 and MATE2) for cationic drugs including Metformin. PMAT, OCT1 and OCT3 are expressed in Intestine and may be involved in Intestinal transport of metformin. OCT1, OCT3 and MATE1 expression in liver may facilitate hepatic uptake of metformin. In Kidney OCT1, OCT2 and PMAT may act as influx transporter while MATE1 and MATE2 may act as efflux transporters. Metformin is the first line of drug for diabetes and may have beneficial effects in cancer treatment. Expression profile of metformin transporters may have crucial role in pharmacokinetics of the drug. At present there is very limited data for the expression of these transporters in different cell lines and db/db mice. No in-vitro data is present for comparative expression of these transporters in primary endothelial cells vs. cancerous cells and effect of high glucose/metformin treatment on the expression of drug transporters is still unknown. Therefore, we aimed to investigate the expression levels of OCT1, OCT2, OCT3, MATE1, MATE2 and PMAT in normal/cancerous cell lines as well as mice organs (intestine, liver and kidney) under normo/hyper-glycemic condition and low/high dosage of metformin treatment.

Material and methods

Different cancerous/non-cancerous cell lines (HUVECs, MCF7, PA1, Huh7, HEK293T and MMECs) were cultured in normal/high glucose mediums and treated with low/high dosage of metformin for 7 days. Cells in early passages (P3 to P6) were used and experiments were replicated five times. Mice samples (liver, kidney and small intestine) were collected from wild type (C57BL/6J) and db/db mice after treatment with metformin for 6–8 weeks. Total RNA and proteins were isolated from cell line/mice organ samples and gene/protein expressions were estimated by using real-time PCR and western blotting. Gene expressions were leveled by the endogenous controls (beta-actin and GAPDH) and comparative CT values were estimated. Relative gene expressions were calculated through 2-(ΔΔCT) method. Western blot analysis was done after normalizing densitometry data of transporter proteins with endogenous control protein (β-actin or GAPDH).


We detected expression of all selected metformin transporters in endothelial cells and in majority of cancer cell lines. Comparative gene expressions of metformin transporters in all of the selected cell lines were estimated. The levels of OCT1/OCT2 expressions between non-cancerous/cancerous cell lines were significantly modulated (P


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