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Although some guanidine compounds were reported as superior substrates for organic cation transporter (OCT)2 than OCT1, it was unclear whether this guanidino group was an important factor in determining the specificity of hOCT1 and hOCT2. Using HEK293 cells transfected with human (h)OCT1 or hOCT2 cDNA, we assessed the role of hOCT1 and/or hOCT2 in the transport of guanidine compounds such as uremic toxins and therapeutic agents. Guanidine, creatinine and aminoguanidine more markedly inhibited the uptake of [14C]tetraethylammonium (TEA) by hOCT2 than by hOCT1. [14C]TEA uptake by hOCT2, but not hOCT1, was trans-stimulated by unlabeled guanidine, methylguanidine, creatinine, aminoguanidine and phenylguanidine. In patients with renal failure, the impairment of hOCT2 might decrease the excretion of guanidine, methylguanidine, and creatinine as uremic toxins. The uptake of aminoguanidine, a candidate for an anti-diabetic agent, was enhanced by hOCT2 with the Michaelis constant (Km) of 4.10 ± 0.35 mM. Metformin, which was also an anti-diabetic agent, and creatinine more potently inhibited the uptake of [14C]aminoguanidine by hOCT2 than that by hOCT1. Aminoguanidine had little impact on the uptake of [14C]metformin by hOCT1, but inhibited that by hOCT2 with the IC50 of 1.49 ± 0.14 mM. These results indicated that the specificity of hOCT1 and hOCT2 was not determined simply by guanidino group. Among guanidine compounds, aminoguanidine was identified as a new superior substrate for hOCT2.