Health Matters

Thiamine Intestinal Transport and Related Issues: Recent Aspects

Gianguido Rindi1 and Umberto Laforenza
P.S.E.B.M. 2000, Vol 224:246–255]

Abstract. In the intestinal lumen thiamine is in free form and very low concentrations. Absorption takes place primarily in the proximal part of the small intestine by means of a dual mechanism, which is saturable at low (physiological) concentrations and diffusive at higher. Thiamine undergoes intracellular phosphorylation mainly to thiamine pyrophosphate, while at the serosal side only free thiamine is present. Thiamine uptake is enhanced by thiamine deficiency, and reduced by thyroid hormone and diabetes.
The entry of thiamine into the enterocyte, as evaluated in brush border membrane vesicles of rat small intestine in the absence of H+ gradient, is Na+- and biotransformation-independent, completely inhibited by thiamine analogs and reduced by ethanol administration and aging.

The transport involves a saturable mechanism at low concentrations of vitamin and simple diffusion at higher.
Outwardly oriented H+ gradients enhance thiamine transport, whose saturable component is a Na+-independent electroneutral uphill process utilizing energy supplied by the H+ gradient, and involving a thiamine/ H+ 1:1 stoichiometric exchange.
(so does this mean the ATP pump?)

The exit of thiamine from the enterocyte, as evaluated in basolateral membrane vesicles, is Na+-dependent, directly coupled to ATP hydrolysis by Na+-K+-ATPase, and inhibited by thiamine analogs. Transport of thiamine by renal brush border membrane vesicles is similar to the intestinal as far as both H+ gradient influence and specificity are concerned. In the erythrocyte thiamine transport is a Na+-independent, electroneutral process yet with two components: saturable, prevailing at low thiamine concentrations, and diffusive at higher.

The saturable (specific) component is missing in patients of the rare disease known as thiamine-responsive megaloblastic anaemia (TRMA), producing a general disturbance of thiamine transport up to thiamine deficiency. The TRMA gene is located in chromosome 1q23.3.

Recently, the thiamine transporter has been cloned: it is a protein of 497 aminoacid residues with high homology with the reduced-folate transporter.

http://dx.doi.org/10.1046/j.1525-1373.2000.22428.x

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Regulation of reduced-folate transporter-1 in retinal pigment epithelial cells by folate
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15875363&dopt=Abstract

high folate levels in blood downregulated the folate transporter(and its asociated mRNA levels)..as expected
"Steady-state levels of Reduced-folate transporter-1 (RFT-1) mRNA and protein(ie the actual RTF transporter) decreased significantly in the presence of excess folate.
CONCLUSIONS: Excess folate levels downregulate RFT-1 in RPE."
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my RBC folate is over high?? without any supps(even with avoidance of added folate ) My Mum's RBC folate is over the top of normal too, not far but always over both of us. For some unknown to me reason we have never had our serum folate measured?..

http://jasn.asnjournals.org/cgi/content/full/14/5/1314

seems to be saying that serum folate is usually normal even if RBC folate is high..and its genetic..as I suspected ..and to do with glutamate something...???

and says no influence on serum folate, B12 or anything else.. so not relevant.. or as as far as known :-no effect of this genetic high red blood cell(RBC) folate
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also see following post(s) ~
http://tealady-health.blog.co.uk/2006/09/09/thiamin_transporters~1111873
edit [Bob]
http://www.journals.uchicago.edu/-AJHG/journal/issues/v77n1/42232/42232.html

Acta Paediatrica
Issue: Volume 95, Number 1 / January 2006
Pages: 99 - 104
Thiamine-responsive megaloblastic anaemia syndrome: Long-term follow-up and mutation analysis of seven families
Christopher J. Ricketts A1, Jayne A. Minton A1, Jacob Samuel A2, Indra Ariyawansa A3, Jerry K. Wales A4, Ivan F. Lo A5, Timothy G. Barrett A1
Abstract:
Aim: Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is the association of diabetes mellitus, anaemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data. We aimed to study genotype–phenotype relationships and long-term follow-up in our cohort. Methods: We have studied 13 patients from seven families and have follow-up data for a median of 9 y (2–30 y).
Results: All patients originated from Kashmir or Punjab, and presented with non-immune, insulin-deficient diabetes mellitus, sensorineural deafness and a variable anaemia in the first 5 y of life, the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow. The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d, but during puberty thiamine supplements became ineffective, and almost all patients require insulin therapy and regular blood transfusions in adulthood.
All patients are homozygous for mutations in the SLC19A2 gene. We have identified a novel missense mutation (T158R) that was excluded in 100 control alleles.
Conclusion: Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements; however, most patients become fully insulin dependent after puberty.
 A mutation screening strategy is feasible and likely to identify mutations in almost all cases.
 My comment:  Puberty stopping the thiamin working is interesting; one thing is the oestrogen binding the thiamin, I presume testosterone may be also?...and maybe growth hormone had some effect as well?.. expect it to from some people's reaction to growth hormone, but couldnt find anything
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1: Pflugers Arch. 2004 Feb;447(5):641-6. Epub 2003 May 6. Links
SLC19: the folate/thiamine transporter family.
Ganapathy V, Smith SB, Prasad PD.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, GA 30912-2100, Augusta, USA, vganapat@mail.mcg.edu

The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H(+)/OH(-) gradient.
SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH.
SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine.
This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.

BOB_sent via email.. full text and pdf, titled 'the ABC of solute carriers'. or thiamin/folate transporters

some notes of interest in article:
"SLC19A1 expression... In addition, the activity and expression of the transporter are decreased by nitric oxide and hyperglycemia [18, 31]. "
as I suspected the high blood glucose-diabetes type2 link is maybe correlated wih thiamin levels, ie higher glucose levels reduce this transporter, so reduce thiamin levels..also higher NO reduce thiamin levels.

"Role of SLC19 gene family members in the homeostasis of folate and thiamine.
The SLC19 gene family plays an important role in the transport and homeostasis of folate and thiamine in the body. Since SLC19A1 has also been shown to transport mono- and pyro-phosphate derivatives of thiamine , all three members of the SLC19 gene family may play a role in the homeostasis of thiamine. (My comment:and note above (same paper)  SLC19A1 is  decreased by hyperglycemia and NO)
It is quite evident that the role of these transporters in non-polarized cells is to mediate the influx of folate and thiamine into the cells. However, in cells that mediate the transcellular transfer of these vitamins (e.g., the absorptive cells of the intestine and kidney, the syncytiotrophoblast in the placenta, and the retinal pigment epithelium), the exact role of these transporters is dependent on their polarized distribution in the apical membrane versus the basolateral/basal membrane. The distribution of SLC19A2 and SLC19A3 in these polarized cells has not yet been investigated and therefore it is difficult to predict their exact role in the transcellular movement of thiamine and consequently in thiamine homeostasis of the whole organism. On the other hand, recent advances in the area of subcellular localization of SLC19A1 in polarized cells have enhanced our understanding of the role of this transporter in the transcellular movement of folate"
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Related:
The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter.

Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome.   this one mentions thyroid
"At age 19, a thiamine-responsive normocytic anemia was discovered. She was diagnosed with autoimmune thyroiditis at 20 years and she experienced a psychotic episode associated with a mood disorder at age 21. With oral thiamine therapy, her insulin requirement decreased by 30% over a 20 month period"
Interestingly, 30% is approx the amount I have had to reduce my thyroid meds by since injecting myself with 20mg daily of thiamin( I think I've settled on). but its too early to say, and it could be a coincidence or another factor (EG. I added in kelp too).
Suggestion: we usually don't have the same gene mutation or knockout.. BUT if thiamin transporters are affected, then maybe we are seeing some effects of this that may be correctable by high thiamin intake
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Polarized expression of members of the solute carrier SLC19A gene family of water-soluble multivitamin transporters: implications for physiological function
Boulware MJ, Subramanian VS, Said HM, Marchant JS.
Biochem J. 2003 Nov 15;376(Pt 1):43-8
Humans lack biochemical pathways for the synthesis of the micro-nutrients thiamine and folate. Cellular requirements are met through membrane transport activity, which is mediated by proteins of the SLC19A gene family. By using live-cell confocal imaging methods to resolve the localization of all SLC19A family members, we show that the two human thiamine transporters are differentially targeted in polarized cells, establishing a vectorial transport system. Such polarization decreases functional redundancy between transporter isoforms and allows for independent regulation of thiamine import and export pathways in cells.
www.biochemj.org/bj/376/0043/bj3760043.htm
This is where I came across targeting to apical and basolateral membranes......
full text is available
Bob
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