Role of signaling pathways in the regulation of folate transport in ethanol-fed rats

Hamid, Abid; Kaur, Jyotdeep

doi:10.1016/j.jnutbio.2008.03.004

Cited by 18 publications

(17 citation statements)

References 26 publications

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“…Moreover, dibutyryl cAMP, a compound that increases the intracellular cAMP levels, resulted in a significant increase in folic acid uptake, with 2.0‐fold higher increase in the ethanol‐fed group than in the control group. This suggested that cAMP may be an important regulatory component of signaling cascade that is affected in chronic alcoholism [52]. Moreover, atropine, which causes decreased intracellular cAMP levels by inhibiting the activity of adenylyl cyclase, inhibited folic acid transport in both groups of rats, but the decrease was less (51%) in the case of alcoholic rats (Fig.…”

Section: Influence Of Alcoholism On the Membrane Transport And Bioavamentioning

confidence: 99%

“…Moreover, atropine, which causes decreased intracellular cAMP levels by inhibiting the activity of adenylyl cyclase, inhibited folic acid transport in both groups of rats, but the decrease was less (51%) in the case of alcoholic rats (Fig. 3) [52]. Importantly, many groups have demonstrated, in models of chronic alcoholism, that both the initial deconjugation and the subsequent transport of monoglutamic folate are impaired in alcoholic individuals [101].…”

Section: Influence Of Alcoholism On the Membrane Transport And Bioavamentioning

confidence: 99%

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New perspectives on folate transport in relation to alcoholism‐induced folate malabsorption – association with epigenome stability and cancer development

2009

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Folates are members of the B-class of vitamins, which are required for the synthesis of purines and pyrimidines, and for the methylation of essential biological substances, including phospholipids, DNA, and neurotransmitters. Folates cannot be synthesized de novo by mammals; hence, an efficient intestinal absorption process is required. Intestinal folate transport is carrier-mediated, pH-dependent and electroneutral, with similar affinity for oxidized and reduced folic acid derivatives. The various transporters, i.e. reduced folate carrier, proton-coupled folate transporter, folate-binding protein, and organic anion transporters, are involved in the folate transport process in various tissues. Any impairment in uptake of folate can lead to a state of folate deficiency, the most prevalent vitamin deficiency in world, affecting 10% of the population in the USA. Such impairments in folate transport occur in a variety of conditions, including chronic use of ethanol, some inborn hereditary disorders, and certain diseases. Among these, ethanol ingestion has been the major contributor to folate deficiency. Ethanolassociated folate deficiency can develop because of dietary inadequacy, intestinal malabsorption, altered hepatobiliary metabolism, enhanced colonic metabolism, and increased renal excretion. Ethanol reduces the intestinal and renal uptake of folate by altering the binding and transport kinetics of folate transport systems. Also, ethanol reduces the expression of folate transporters in both intestine and kidney, and this might be a contributing factor for folate malabsorption, leading to folate deficiency. The maintenance of intracellular folate homeostasis is essential for the one-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Ethanol, a toxin that is consumed regularly, has been found to affect the methylation of DNA. In addition to its effect on DNA methylation due to folate deficiency, ethanol could directly exert its effect through its interaction with one-carbon metabolism, impairment of methyl group synthesis, and affecting the enzymes regulating the synthesis of S-adenosylmethionine, the Abbreviations 5,10-CH 2

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Section: Influence Of Alcoholism On the Membrane Transport And Bioavamentioning

confidence: 99%

Section: Influence Of Alcoholism On the Membrane Transport And Bioavamentioning

confidence: 99%

New perspectives on folate transport in relation to alcoholism‐induced folate malabsorption – association with epigenome stability and cancer development

2009

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“…Therefore in addition to its direct effects on pancreatic dysfunction, the ethanol might impart its effects through associated folate deficiency and disturbed one carbon metabolism. We have earlier shown the transcription regulation of the folate transporters to be the main molecular mechanism of alcohol associated poor absorption of folate in intestine, colon, and kidney [4], [15]–[20]. Recently, Said et al [21] have demonstrated molecular mechanisms of folate transport regulation in pancreatic acinar cells during folate deficient conditions and have also shown the reduced mRNA expression of the folate transporters in the pancreatic acinar cells during chronic alcoholism.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Molecular Mechanisms of Folate Transport in Rat Pancreas; Interference with Ethanol Ingestion

2011

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Folic acid is an essential nutrient that is required for one-carbon biosynthetic processes and for methylation of biomolecules. Deficiency of this micronutrient leads to disturbances in normal physiology of cell. Chronic alcoholism is well known to be associated with folate deficiency which is due, in part to folate malabsorption. The present study deals with the mechanistic insights of reduced folate absorption in pancreas during chronic alcoholism. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and the mechanisms of alcohol associated reduced folate uptake was studied in pancreas. The folate transport system in the pancreatic plasma membrane (PPM) was found to be acidic pH dependent one. The transporters proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) are involved in folate uptake across PPM. The folate transporters were found to be associated with lipid raft microdomain of the PPM. Ethanol ingestion decreased the folate transport by reducing the levels of folate transporter molecules in lipid rafts at the PPM. The decreased transport efficiency of the PPM was reflected as reduced folate levels in pancreas. The chronic ethanol ingestion led to decreased pancreatic folate uptake. The decreased levels of PCFT and RFC expression in rat PPM were due to decreased association of these proteins with lipid rafts (LR) at the PPM.

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“…Endothelin-B exerts its effect through Protein Kinase C [29, 30]. Hamid and Kaur [31] revealed the role of PKC in intestinal folate transport during alcohol conditions. Although blocking any of the steps in the ET-ETB-NOS-NO-PKC pathway eliminates the effect of certain chemicals or nephrotoxicants on transport pathway, just blocking ETB receptor, the first step in signaling is sufficient [15].…”

Section: Discussionmentioning

confidence: 99%

Methods to Evaluate the Effect of Ethanol on the Folate Analogue: Fluorescein Methotrexate Uptake in Human Proximal Tubular Cells

Gowder

McMartin

2009

Advances in Pharmacological Sciences

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Ethanol-induced folate deficiency is due to effects of ethanol on folate metabolism and absorption. We have already shown by using different methods that ethanol interferes with reabsorption of folate from the proximal tubule. In this study, we have used the folate analogue, the fluorescein methotrexate (FL-MTX), in order to evaluate effects of ethanol on FL-MTX uptake by the human proximal tubular (HPT) cells by using a confocal microscope and fluoroskan microplate reader. Since endothelins (ETs) play a major role in a number of diseases and also in the damage induced by a variety of chemicals, we have used endothelin-B (ET-B) and protein kinase-C (PKC) inhibitors to evaluate the role of endothelin in ethanol-mediated FL-MTX uptake by using fluoroskan microplate reader. Confocal microscope and fluoroskan studies reveal that cellular absorption of FL-MTX is concentration-dependent. Moreover, ethanol concentration has an impact on FL-MTX uptake. Fluoroskan studies reveal that the ethanol-induced decrease in FL-MTX uptake is reversed by adding the ET-B receptor antagonist (RES-701-1) or PKC-selective inhibitor (BIM). Thus, we can conclude that ethanol may act via ET and ET in turn may act via ET-B receptor and the PKC signaling pathway to impair FL-MTX transport.

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Role of signaling pathways in the regulation of folate transport in ethanol-fed rats

Cited by 18 publications

References 26 publications

New perspectives on folate transport in relation to alcoholism‐induced folate malabsorption – association with epigenome stability and cancer development

New perspectives on folate transport in relation to alcoholism‐induced folate malabsorption – association with epigenome stability and cancer development

Biochemical and Molecular Mechanisms of Folate Transport in Rat Pancreas; Interference with Ethanol Ingestion

Methods to Evaluate the Effect of Ethanol on the Folate Analogue: Fluorescein Methotrexate Uptake in Human Proximal Tubular Cells

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