The Intestinal Absorption of Folates

Visentin, Michele; Diop-Bove, Ndeye; Zhao, Rongbao; Goldman, I. David

doi:10.1146/annurev-physiol-020911-153251

Cited by 163 publications

(128 citation statements)

References 129 publications

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“…Although human proton-coupled folate transporter plays a key role in the intestinal absorption of folic acid (Visentin et al, 2014), Urquhart et al (2010) reported that human proton-coupled folate transporter mRNA levels decreased in patients receiving PPIs. Thus, it is likely that the decreased oral absorption of folic acid caused by PPIs contributed to the development of hematologic toxicity associated with pemetrexed; however, we demonstrated that the coadministration of other PPIs was not a significant risk factor for hematologic toxicity associated with pemetrexed (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Ikemura

Hamada

Kaya

et al. 2016

Drug Metabolism and Disposition

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Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (K m = 68.3 6 11.1 mM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC 50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 6 0.17 mM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interactioninduced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

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Section: Discussionmentioning

confidence: 99%

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Ikemura

Hamada

Kaya

et al. 2016

Drug Metabolism and Disposition

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“…RFC acts at a physiological pH in the distal small intestine and the colon, whereas PCFT mediates the intestinal absorption of dietary folates at acidic pH in the proximal half of the small intestine [3]. After intestinal uptake, most of the folate is reduced and methylated and enters the circulation mainly as 5-MTHF.…”

Section: Folate Transport and Metabolismmentioning

confidence: 99%

Can folic acid have a role in mitochondrial disorders?

Ormazábal

Casado

Molero-Luís

et al. 2015

Drug Discovery Today

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“…Mammals meet their biosynthetic needs for one-carbon donors by absorption of dietary folates mediated by the protoncoupled folate transporter (PCFT) 2 (SLC46A1) (1,2). Mutations in the PCFT gene that result in loss of the protein or its function are the basis for hereditary folate malabsorption (OMIM 229050), a rare autosomal recessive disorder (1,3).…”

mentioning

confidence: 99%

Identification of an Extracellular Gate for the Proton-coupled Folate Transporter (PCFT-SLC46A1) by Cysteine Cross-linking

Zhao

Najmi

Fiser

et al. 2016

Journal of Biological Chemistry

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Mammals meet their biosynthetic needs for one-carbon donors by absorption of dietary folates mediated by the protoncoupled folate transporter (PCFT) 2 (SLC46A1) (1, 2). Mutations in the PCFT gene that result in loss of the protein or its function are the basis for hereditary folate malabsorption (OMIM 229050), a rare autosomal recessive disorder (1, 3).PCFT transports protons along with folates as reflected in the current and acidification accompanying folate transport in oocytes that express this transporter (1, 4 -6). Structure-function studies, based on site-directed and random mutagenesis, have begun to define residues and domains that play a key role in PCFT function. Elucidation of the secondary structure of PCFT, along with the residues that contribute to the aqueous translocation pathway, have been documented by the substituted cysteine accessibility method (7). The protein consists of 12 transmembrane helices, divided in half by a large intracellular loop, with C and N termini oriented into cytoplasm (8 -10). Residues critical to folate/antifolate binding, proton coupling, and proton binding have been identified (5,(11)(12)(13). The roles of residues in the 2nd, 4th transmembrane domains (TMDs), and the loop connecting the 2nd and 3rd TMDs have been studied (14,15). Analyses of the functional defects that occur in subjects with hereditary folate malabsorption have provided insights into residues important to PCFT protein folding, stability, and/or trafficking to the cell membrane, substrate binding, and oscillation of the carrier between its conformational states (13, 16 -20).PCFT expression is limited to eukaryotes; there are no closely related proteins present in archaea or bacteria, so that a highresolution x-ray crystal structure with a high level of sequence identity is not available that would facilitate a structure/function analysis of the human or rodent proteins. Rather, homology modeling has identified the structure of the bacterial homolog, the glycerol-3-transporter, GlpT, as having a protein structure most like PCFT despite a low (14%) sequence identity (5,10,21). In this model, the transporter is in a conformation that is closed to the outside and open to the inside. According to the alternative access model, PCFT oscillates between this conformation and a conformation that is closed to the inside and open to the outside. This computational model has been used for correlation with functional data and for structural predictions as in the current study (5, 12-14, 21, 22).In this inward facing homology model of PCFT, TMD-1, -2, -7, and -11 are predicted to cluster together in proximity to the extracellular interface to form an extracellular gate. To confirm the presence of such a gate, Cys pairs predicted to be in proximity were introduced into these TMDs at locations near the extracellular surface. The possibility that the pairs are sufficiently close to be cross-linked and/or form a complex was evaluated by assessment of function, which should be decreased when the mobility of the gate is r...

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The Intestinal Absorption of Folates

Cited by 163 publications

References 129 publications

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Can folic acid have a role in mitochondrial disorders?

Identification of an Extracellular Gate for the Proton-coupled Folate Transporter (PCFT-SLC46A1) by Cysteine Cross-linking

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