Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate.

Molecular Pharmacology
Michele VisentinI David Goldman

Abstract

5-Aminoimidazole-4-carboxamide riboside (AICAR), an agent with diverse pharmacological properties, augments transport of folates and antifolates. This report further characterizes this phenomenon and defines the mechanism by which it occurs. Exposure of HeLa cells to AICAR resulted in augmentation of methotrexate, 5-formyltetrahydrofolate, and 5-methyltetrahydrofolate initial rates and net uptake in cells that express the reduced folate carrier (RFC). This did not occur in cells that express only the proton-coupled folate transporter and accumulated folates by this mechanism. Transport stimulation correlated with the accumulation of 5-aminoimidazole-4-carboxamide ribotide monophosphate (ZMP), the monophosphate derivative of AICAR, within cells as established by liquid chromatography. When ZMP formation was blocked with 5-iodotubercidin, an inhibitor of adenosine kinase, folate transport stimulation by AICAR was absent. When cells first accumulated ZMP and were then exposed to 5-iodotubercidin or AICAR-free buffer, the ZMP level markedly decreased and folate transport stimulation was abolished. Extracellular ZMP inhibited RFC-mediated folate influx, and the presence of intracellular ZMP correlated with inhibition of folate efflu...Continue Reading

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Citations

Jul 25, 2013·Cancer Chemotherapy and Pharmacology·Michele VisentinI David Goldman
Oct 4, 2012·Clinical Medicine Insights. Oncology·Annabelle L RoddTom C Karagiannis
Feb 12, 2014·Annual Review of Physiology·Michele VisentinI David Goldman
Mar 26, 2014·Expert Opinion on Investigational Drugs·Alessandra DondiStefano Sacchi
Nov 4, 2015·Digestive Diseases and Sciences·Shari S RogalUNKNOWN Electronically Retrieved Cohort of HCV Infected Veterans Study Group
Jan 8, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Larry H MatherlyZhanjun Hou
Sep 4, 2015·The Journal of Pharmacology and Experimental Therapeutics·Michele VisentinGerd A Kullak-Ublick
Sep 13, 2019·Nature·Rutger D LuteijnDavid H Raulet
Dec 28, 2018·The Journal of Experimental Medicine·Yuxiang Zheng, Lewis C Cantley

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