Disease relevance of Slc19a1

• Furthermore, expression of RK-MTX-1 in MDCK cells enhanced methotrexate toxicity in these cells fivefold [1].
• Analysis of a fusion protein of RK-MTX-1 and the influenza virus hemagglutinin epitope by immunoblotting revealed a major band at 72 kDa within the cell membrane but not in the soluble fraction of transfected MDCK [1].
• BACKGROUND: Methotrexate (MTX) is used in the treatment of rheumatic disease, sometimes along with non-steroidal anti-inflammatory drugs (NSAIDs), and is actively co-transported with H+ in the small intestine, mediated by a reduced folate carrier (RFC) [2].

Psychiatry related information on Slc19a1

• Three of the cell lines (RFC1, EcoC-3, and SalC) were highly tumorigenic and induced tumors with a short latency period; two cell lines (HindG-2 and AccH-1) were also tumorigenic, but the latency period was significantly longer [3].

High impact information on Slc19a1

• The basis of this strategy is that methotrexate-alpha-peptides are inefficient substrates for the reduced folate carrier (RFC) and hence cannot be internalized by cells [4].
• Uptake of [3H]MTX and [3H]folinic acid, but not [3H]folic acid, by H35 cells was inhibited in a dose-related manner by PT523, suggesting that penetration of the cell probably involves, at least in part, active transport by the MTX/reduced folate carrier [5].
• However, influx of [(3)H]MTX by this system is 3-4-fold higher at pH 6 than at pH 7.5, the optimum for RFC-1-mediated folate compound transport [6].
• The relative inhibition of influx of [(3)H]MTX by the organic anions, probenecid, and PO(4) was different than for RFC-1 mediated influx [6].
• This downregulation of the acid pH dependent system and concomitant upregulation of the RFC-1 mediated system markedly altered pH dependency for influx of [(3)H]MTX in these transfectants compared to that seen in untransfected cells [6].

Biological context of Slc19a1

• This was contrasted with the results of transfection of the same RFC1 construct into an L1210 murine leukemia cell line bearing a nonfunctional endogenous carrier [7].
• Recently, the rat genome project revealed the genomic sequence of slc19a1, coding for the methotrexate carrier-1, identical to the reduced folate carrier-1 of humans, on rat chromosome 20 [8].
• We conclude that the major route for internalization at a physiological pH of folate compounds in FR3T3 cells is by an acid pH-dependent carrier-mediated system independent of RFC-1 expression and is downregulated by oncogene expression [6].
• The increase in RFC-1 expression in FR3T3Hras cells appears to result from a higher rate of transcription of the gene in these cells as determined by a luciferase reporter gene assay of RFC-1 promoter activity [6].
• RT-PCR analysis indicated gene expression of Oat2, Oatplal, Oatpla4, Oatplb2, Rfc-1/MTX-1, FOLR, Mrp1-6, mdr1, and Lrp [9].

Anatomical context of Slc19a1

• Preservation of folate transport activity with a low-pH optimum in rat IEC-6 intestinal epithelial cell lines that lack reduced folate carrier function [10].
• Transient transfection of the GFP-mutated RFC constructs into RFC-null HeLa cells confirmed their lack of transport function [10].
• Previous studies from our laboratory and others have demonstrated that folate absorption from the small intestine is mediated via the reduced-folate carrier (RFC) [11].
• Little, however, is known about the actual contribution of the RFC system toward total folate uptake by the enterocytes [12].
• In situ hybridization showed a similar pattern of RFC message distribution along crypt/villus axis in suckling and adult rat jejunum [11].

Associations of Slc19a1 with chemical compounds

• Here, we report on the cloning of the cDNA for the renal methotrexate carrier isoform-1 (RK-MTX-1) and its functional characterization [1].
• 4. These data indicate that RFC1 can exhibit two distinct types of folate transport activities in intestinal cells that must depend on tissue-specific modulators [7].
• 4. Transfection of this cell line with an RFC1 construct resulted in clones exhibiting increased MTX uptake at both the pHs and high folic acid uptake only at the low pH [7].
• NSAIDs, except salicylate, were potent inhibitors of rOat3 (K(i) of 1.3-19 microM), but weak inhibitors of RFC-1 (K(i) of 70-310 microM) [13].
• These results suggest that rOat3 and RFC-1 are almost equally involved in the uptake of MTX by the kidney slices, whereas RFC-1 is responsible for the renal uptake of 5-methyltetrahydrofolate [13].

Analytical, diagnostic and therapeutic context of Slc19a1

• Western blot analysis of BBM protein and real-time PCR showed RFC protein and mRNA levels, respectively, to be significantly (P < 0.01 for both) higher in suckling compared with weanling rats, which were in turn significantly (P < 0.01 for both) higher than that in adult rats [11].
• Quantitative evaluation of the drug-drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier [13].

References