Roles OF SLC Transporters In Drug Disposition And Disease Control In Vitro And In Vivo Investigations On SLC22A8 And SLC2A5

SLC(solute carrier)family transport proteins play important roles in the absorption and transport of amino acids,nucleotides,sugars,fatty acids,natural products and drugs.For xenobiotics,the expression and function variations of SLC family transporters affect pharmacokinetics,pharmacodynamics and toxicity of many drugs and natural products including food components.For essential nutrients(glucose,amino acids,vitamins,etc.),SLC family transporters play an important role in health and disease states.Using SLC22A8(OAT3)and SLC2A5(GLUT5)as examples,the present study aimed to investigate:(1)OAT3-mediated uptake of steviol acyl glucuronide(SVAG)and its interaction potential with commonly used drugs:(2)examine role of GLUT5 in tumor cell proliferation and its potential as a drug target for cancer-metablism based antitumor therapies.Interaction of OAT3-Mediated Uptake of SAVG with Selected Drugs Organic anion transporter 3(OAT3),encoded by SLC22A8 gene,plays a critical role in the renal excretion of many xenobiotics.Since steviol acyl glucuronide(SVAG),an OAT3 substrate,is the major circulating metabolite after oral ingestion of steviol glycosides and is excreted into the urine,inhibition of OAT3 activity may alter pharmacokinetic profiles of SVAG.The present study showed that drugs such as probenecid and glimepiride displayed potent inhibition toward OAT3-mediated SAVG transport in vitro,with IC50 values of 4.9 and 0.8?M,respectively.No species differences were observed between human and rat.Probenecid and glimepiride could significantly elevate plasma concentrations of SVAG after oral administration of rebaudioside A,with significant increases in plasma maximum(Cmax)and area under the plasma time-concentration curve(AUC)values.The inhibitory effect on OAT3-mediated SVAG transport exemplified a unique case of food-drug interaction mediated by the metabolite of a food additive.Role of GLUT5 in the Proliferation of Selected Tumor Cell Lines Warburg effect describes a phnomenon where energy consumption is high in cancer cells.More glucose consumption in cancer cells results in glucose deficiency in the tumor microenvironment.To supplement for additional energy,cancer cells would take advantage of fructose as an alternative sugar source.Sugar molecules' transmembrane transport relies on the function of sugar transporters,for example,GLUT5(encoded by SLC2A5)for fructose,respectively.It has been shown that the expression of SLC2A5 in cancerous tissues of ovarian cancer,lung adenocarcinoma,glioma,and acute myeloid leukemia cell is significantly higher than that of normal tissues or cells.Moreover,decreasing the expression of SLC2A5 by gene silencing/knockout could significantly decrease the proliferation of tumor cells.In this study,a monoclonal cell line that can stably express GLUT5 has been established and validated.GLUT5 mediated uptake of fructose can be monitored by LC-MS/MS.Inhibitory effect of 111 compounds,including natural remediess,small molecules,and glycosides or glucuronidation conjugates were investigated against GLUT5 activity,among those 14 compounds were found capable of inhibiting GLUT5-mediated fructose uptake.The growth and proliferation of human tumor cell lines such as SGC7901(gastric cancer),HeLa(cervical cancer),MCF-7(breast cancer),LoVo(colon cancer)and HCT-116(colon cancer)were dependent on fructose concentrations in culture media.Under different culture conditions for the above cell lines,it was found that scutellarin(a glucuronide)and dagagliflozin(a small molecule SGLT2 inhibitor)displayed a broad spectrum of antitumor activities.ConclusionIn the present study,roles of SLC transporters in the disposition of steviol acyl glucuronide(SVAG)and tumor proliferation were investiagted.SLC22A8-mediated uptake of SVAG could be inhibitoed by probenecid(an anti-hyperuricemia drug)and glimepiride(an anti-hypoglycemic drug)in vitro as well in vivo in rats.In parallel,SLC2A5(GLUT5)mediated fructose transport played an important role in tumor cell grwoth and proliferation and this transporter activity could be inhibited by a number of compounds.This finding provides a solid foundation for future research and it is anticipated that a novel therapy targeting tumor metabolism via fructose transport will be identified.