Vitamin Transporters. How Critical Are They?

It is a fact that humans have lost the ability to synthesize most water soluble vitamins.  We therefore rely on exogenous sources to provide these precious substances that are essential for normal human health and wellbeing [1].  Absorbing these vitamins and bringing them to their sites of action, both systemic and local, involve complicated cellular pathways and processes extensively using membranes transporters [2, 3]. Indeed vitamin transport and homeostasis are tightly regulated by both uptake and efflux transporters as exemplified at the Blood Brain Barrier where more than 90% of vitamin transfer actually occurs through specialized carrier systems [1].

It is currently known that water soluble ascorbate, biotin, riboflavin, folate, niacin, pyridoxine and thiamine vitamins are absorbed via specific-carrier-mediated processes [4-6]. For instance, folates are co-factors in critical biosynthetic pathways including de novo synthesis of purines and thymidylate, amino acid metabolism and methylation reactions.  Folates and reduced folates can be transported into cells by three identified folate transporters: The reduced folate carrier (RFC, SLC19A1), the proton-coupled folate transporter (PCFT, SLC46A1), and the mitochondrial folate transporter (MFT, SLC25A32). MFT and RFC are ubiquitous. PCFT is the main carrier responsible for intestinal transport of dietary folates. Whereas most antifolates (e.g., methotrexate, talotrexin, raltitrexed, palatrexate, lometrexol) are transported either by RFC alone or by both RFC and PCFT, it was found that pemetrexed has high affinity for PCFT, which then is the major transporter for pemetrexed specifically into cancer cells [7-9]. Another essential nutrient, thiamine with potential fatal outcome in case of severe deficiency is also transported by two distinct thiamine transporters called hTHTR1 (SLC19A2) and hTHTR2 (SLC19A3) that are both widely expressed in various tissues including intestine, kidney, brain and liver [10]. Originally known to the public as beriberi, thiamine deficiency can lead to multiple severe pathologies including Wernicke’s encephalopathy which mainly affecting the central nervous system [11].  A very dramatic reminder of the importance of preserving good thiamine transport was recently brought to light by the early clinical termination of fedratinib, a very promising Janus Kinase 2 inhibitor, following reports of Wernicke’s encephalopathy in myelofibrosis patients [12]. In the word of the authors responsible for elucidating the mechanism of these severe adverse events: “ The results from these studies…highlight the needs to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters” [13].

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2.            Said, H.M., Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas. Am J Physiol Gastrointest Liver Physiol, 2013. 305(9): p. G601-10.

3.            Said, H.M., Water-soluble vitamins. World Rev Nutr Diet, 2015. 111: p. 30-7.

4.            Manzetti, S., J. Zhang, and D. van der Spoel, Thiamin function, metabolism, uptake, and transport. Biochemistry, 2014. 53(5): p. 821-35.

5.            Burzle, M., et al., The sodium-dependent ascorbic acid transporter family SLC23. Mol Aspects Med, 2013. 34(2-3): p. 436-54.

6.            Hediger, M.A., et al., The ABCs of membrane transporters in health and disease (SLC series): introduction. Mol Aspects Med, 2013. 34(2-3): p. 95-107.

7.            Alvarez-Fernandez, C., et al., Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC). Invest New Drugs, 2014. 32(2): p. 377-81.

8.            Wang, Y., et al., A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed. Cancer Res, 2002. 62(22): p. 6434-7.

9.            Zhao, R., et al., The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol, 2008. 74(3): p. 854-62.

10.          Bukhari, F.J., et al., Effect of chronic kidney disease on the expression of thiamin and folic acid transporters. Nephrol Dial Transplant, 2011. 26(7): p. 2137-44.

11.          Sechi, G. and A. Serra, Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol, 2007. 6(5): p. 442-55.

12.          Zhang, M., et al., A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol, 2014. 54(4): p. 415-21.

13.          Zhang, Q., et al., The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy. Drug Metab Dispos, 2014. 42(10): p. 1656-62.