Analysis on drug transporters-mediated interaction between drugs and metformin / 中国基层医药

Objective:To investigate the potential drug interactions of outpatient prescriptions containing metformin combined with other drugs from the perspective of drug transporters.Methods:The prescriptions containing metformin that were used in the Outpatient Department of Hainan General Hospital, China between July and December 2019 were collected. The potential interaction between drugs and metformin used in the prescriptions was analyzed according to drug instructions, Drugbank, PubMed databases.Results:A total of 15 568 outpatient prescriptions containing metformin were collected, including 9 146 prescriptions for male patients and 6 422 prescriptions for female patients. A total of 14 902 prescriptions contained combined medication. The drugs used in combination included other hypoglycemic drugs, antiplatelet drugs, antihypertensive drugs, lipid-lowering drugs, and neuroprotective drugs. The drug transporters including aspirin, atorvastatin calcium, repaglinide, bisoprolol, metoprolol and clopidogrel had a potential interaction with metformin. There were 11 614 prescriptions containing drug transporters and metformin, including 5 938 prescriptions inhibiting organic cation transporter 1 and 5676 prescriptions inhibiting organic cation transporter 2.Conclusion:There is no incompatibility between the outpatient prescriptions containing metformin and the commonly used drugs for chronic diseases, but the outpatient doctors do not have enough knowledge about dose adjustment caused by potential interaction.

Research progress of magnesium ion and its transporters in tumors / 肿瘤

In recent years, researchers have found that magnesium ion homeostasis imbalance is common in tumor cells, and the deficiency and supplement of magnesium ion can affect the occurrence and development of tumor. As an abundant divalent cation in cells, magnesium ion plays an important role in maintaining genetic stability, metabolism, cell growth and proliferation, signal transduction and other physiological processes. Magnesium ion homeostasis is regulated by a variety of transporters, and the research reports on the changes of magnesium ion transporters expression leading to the imbalance of magnesium ion homeostasis which affects the occurrence, development and treatment prognosis of tumors are increasing year by year. In this article, magnesium ion and its related transport proteins include magnesium ion transient receptor potential melastatin (TRPM) protein, magnesium transporter (MagT) protein, cyclin and cystathionine beta-synthase (CBS) domain divalent metal cation transport mediator (CNNM) protein and solute carrier (SLC) protein and other related reports in tumors are summarized, with the purpose of providing ideas for exploring whether magnesium ion and its transporters can become new targets for tumor diagnosis, treatment and prognosis.

Changes in expression of spinal divalent metal transporter 1 during remifentanil-induced hyperalgesia in a rat model of incisional pain / 中华麻醉学杂志

Objective To evaluate the changes in the expression of spinal divalent metal transporter 1 (DMT1) during remifentanil-induced hyperalgesia in a rat model of incisional pain.Methods Thirtytwo male Sprague-Dawley rats,weighing 240-260 g,aged 2-3 months,were randomly divided into 4 groups (n =8 each) using a random number table:control group (group C),incisional pain group (group I),remifentanil group (group R),and incisional pain + remifentanil group (group I+R).In group C,normal saline was infused for 60 min at a rate of 0.1 ml · kg-1 · min-1.A 1-cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the left hindpaw in sevoflurane-anesthetized rats,and normal saline was infused intravenously for 60 min at a rate of 1.0 μg · kg-1 · min-1 at the same time in group I.In group R,remifentanil was infused for 60 min at a rate of 1.0 μg · kg 1 · min-1 In group I+R,the model of incisional pain was established,and remifentanil was simultaneously infused for 60 min at a rate of 1.0 μg · kg-1 · min-1.At 24 h before normal saline or remifentanil infusion and 6,24 and 48 h after the end of infusion (T0-3),the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured.All the rats wcrc sacrificed after the last measurement of pain thresholds,and the spinal cord was removed for determination of DMT1 with/without iron-responsive element [DMT1 (+)IRE and DMT1 (-)IRE] expression (by Western blot analysis and immunohistochemistry).Results Compared with group C,the MWT was significantly decreased,and the TWL was significantly shortened at T1-3,and the expression of spinal DMT1 (-) IRE was significantly up-regulated in I,R and I+R groups (P＜0.05).Compared with I and R groups,the MWT was significantly decreased,and TWL was significantly shortened at T1-3,and the expression of spinal DMT1 (-) IRE was significantly upregulated in group I+R (P＜0.05).There was no significant difference in the expression of spinal DMT1 (+) IRE between the four groups (P＞ 0.05).Conclusion Spinal DMT1 (-)IRE activation may be involved in the mechanism underlying remifentanil-induced hyperalgesia in a rat model of incisional pain.

Identification of a kidney-specific mouse organic cation transporter like-1 (mOCTL1)

Organic ion transporters are expressed in various tissues that transport endogenous and exogenous compounds including their metabolites. There are organic anion transporter (OAT), organic cation transporter (OCT), organic anion transporter like protein (OATLP) and organic cation transporter like (OCTL). Considering the variety of charged organic ionic compounds, the existence of numerous isoforms of organic ion transporters can be assumed. In the present study, we have searched for a new isoform in the expressed sequence tag (EST) database using human organic anion transporter 4 (hOAT4) amino acid sequence as a "query". We found a candidate clone (BC021449) from the mouse kidney cDNA library. This clone was identified as an ortholog of ORCTL3 or OCTL-1. The mOCTL1 cDNA consists of 2016 base pairs encoding 551 amino acid residues with 12 putative transmembrane domains. The deduced amino acid sequence of mOCTL1 showed 35 to 40% identity to those of the other members of the OATs and OCTs. According to the tissue distribution, examined by Northern blot analysis, about a 2.4-kb transcript of mOCTL1 was observed in the kidney. About a 90-kDa band was detected when Western blot analysis in the mouse kidney was done by using antibody against synthesized oligopeptide of mOCTL1. The immunohistochemical result showed that mOCTL1 was stained at the glomerulus (the parietal epithelial cells and podocytes), pars recta of proximal tubule, distal convoluted tubules, connecting tubules and collecting tubules. From these results, we conclude that mOCTL1 may be a candidate for an organic ion transporter isoform in the mouse kidney.

Construction of site-directed mutant variants of ATP7B in vitro and their expression / 中华神经科杂志

Objective To study the expression of normal and variant ATP7B proteins, in order to further find the mechanism of Wilson disease. Methods Normal ATP7BcDNA/pcDNA3 was made and mutant variants Arg778Leu/pcDNA3, Gln914Ter/pcDNA3 and Thr935Met/pcDNA3 were constructed by using Quik-Change TM Site-directed Mutagenesis Kit in vitro. A good quality rabbit polyclonal antibody against the N-terminal functional domains of ATP7B was produced and purified, being named rabbit anti-human ATP7Bn33-629 polyclonal antibody. Normal and variant expression plasmids constructed above were transfected into Chinese hamster ovary (CHO) cells. After a 36-hour incubation at 37℃, the transfected CHO cells were collected. Expression of normal and variant ATP7B protein were detected and compared by Western blot analysis of cell lysates using ATP7Bn33-629 antibody. Results Expression of ATP7B normal protein in transfected CHO cells was the same as that of ATP7B variant proteins Arg778Leu and Thr935Met.Gln914Ter variant shortened ATP7B protein to 100 kd and increased the level of expression. Conclusion The mechanism under disorder of copper transport caused by the missense mutations should be not related to the level of expression. The increased level of expression caused by Gln914Ter might be associated with the shortened ATP7B protein that needs less time for translation.