Sajib Abu Ashfaqur, Islam Tasmia, Paul Nilanjana, Yeasmin Sabina
Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
J Genet Eng Biotechnol. 2018 Dec;16(2):769-775. doi: 10.1016/j.jgeb.2018.01.003. Epub 2018 Feb 1.
Metformin is one of the first-line and most widely prescribed drugs to treat type 2 diabetes (T2D). Its clearance from circulation is mostly facilitated by SLC22A2 (OCT2) in the renal cells. SLC22A2 is a polyspecific organic cation transporter and mediate transport of structurally unrelated endogenous and exogenous compounds including many drugs. rs316019 (p.270A > S) is the most common variant of SLC22A2 with a frequency as high as 15% or more in many populations. The 270S form of SLC22A2 clears metformin from circulation at much reduced level compared to the 270A form. If accumulated, metformin increases plasma lactate level in a concentration-dependent manner which can lead to a condition known as metformin-associated lactic acidosis (MALA). MALA is a potentially life-threatening complication with a mortality rate of 30-50%. Pre-existing clinical conditions, such as renal impairment, sepsis, anoxia, etc may make individuals more prone to MALA. In this study, we used computational approaches to investigate the effect of 270A > S change in SLC22A2 on interaction with metformin and other drugs. Based on the structural models, all substrates bind to the same pocket of SLC22A2. The substrates fit better to the binding site of 270A form of SLC22A2. The binding site has a few core interacting residues, among which SER358 appears to be the most important. It is an prediction that the T2D patients, who are under metformin regimen, should be cautious in taking ranitidine (an over-the-counter sold drug) on a regular basis as it may lead to metformin associated lactate accumulation in blood.
二甲双胍是治疗2型糖尿病（T2D）的一线用药且是处方最广泛的药物之一。其从循环系统中的清除主要由肾细胞中的SLC22A2（OCT2）促进。SLC22A2是一种多特异性有机阳离子转运体，介导包括许多药物在内的结构不相关的内源性和外源性化合物的转运。rs316019（p.270A > S）是SLC22A2最常见的变体，在许多人群中的频率高达15%或更高。与270A形式相比，SLC22A2的270S形式从循环中清除二甲双胍的水平大大降低。如果二甲双胍蓄积，会以浓度依赖的方式增加血浆乳酸水平，这可能导致一种称为二甲双胍相关性乳酸性酸中毒（MALA）的病症。MALA是一种潜在的危及生命的并发症，死亡率为30 - 50%。先前存在的临床病症，如肾功能损害、败血症、缺氧等，可能使个体更容易发生MALA。在本研究中，我们使用计算方法研究SLC22A2中270A > S变化对与二甲双胍及其他药物相互作用的影响。基于结构模型，所有底物都结合到SLC22A2的同一口袋中。底物与SLC22A2的270A形式的结合位点更匹配。该结合位点有几个核心相互作用残基，其中SER358似乎是最重要的。据预测，正在服用二甲双胍的T2D患者应谨慎定期服用雷尼替丁（一种非处方销售药物），因为这可能导致血液中二甲双胍相关性乳酸蓄积。
