Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane transport of folates is essential for the survival of all mammalian cells and transport of antifolates is an important determinant of antifolate activity. While a major focus of attention has been on transport mediated by the reduced folate carrier and folate receptors, a very prominent carrier-mediated folate transport activity has been recognized for decades with a low-pH optimum and substrate specificity distinct from that of the reduced folate carrier which operates most efficiently at neutral pH. This low-pH transporter represents the mechanism by which folates are absorbed in the small intestine and it is also widely expressed in other human tissues and solid tumors. Recently, this laboratory discovered the molecular identity of this transporter which is genetically unrelated to the reduced folate carrier. This transporter is proton-coupled, electrogenic, and manifests a substrate specificity that is similar to that of the low-pH transport activity previously described in mammalian cells. The key role this transporter plays in intestinal folate absorption has been confirmed by the demonstration of a mutation in this gene in the rare autosomal recessive disorder, hereditary folate malabsorption. This article reviews (1) the characteristics and prevalence of the low-pH folate transport activity, (2) its relationship to, and properties of, the recently identified Proton-Coupled Folate Transporter (PCFT), (3) the physiological and pharmacological roles of this transporter, particularly with respect to pemetrexed, and (4) the historical controversy, now resolved, on the mechanism of intestinal folate absorption.
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PMID:The molecular identity and characterization of a Proton-coupled Folate Transporter--PCFT; biological ramifications and impact on the activity of pemetrexed. 1734 Jan 71

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling molecules that affect multiple organs; they modulate gut motility and hormone production, and alter vascular tone, glucose metabolism, lipid metabolism, and energy utilization. Changes in fecal bile acids may alter the gut microbiome and promote colon pathology including cholerrheic diarrhea and colon cancer. Key regulators of fecal bile acid composition are the small intestinal Apical Sodium-dependent Bile Acid Transporter (ASBT) and fibroblast growth factor-19 (FGF19). Reduced expression and function of ASBT decreases intestinal bile acid up-take. Moreover, in vitro data suggest that some FDA-approved drugs inhibit ASBT function. Deficient FGF19 release increases hepatic bile acid synthesis and release into the intestines to levels that overwhelm ASBT. Either ASBT dysfunction or FGF19 deficiency increases fecal bile acids and may cause chronic diarrhea and promote colon neoplasia. Regrettably, tools to measure bile acid malabsorption and the actions of drugs on bile acid transport in vivo are limited. To understand the complex actions of bile acids, techniques are required that permit simultaneous monitoring of bile acids in the gut and metabolic tissues. This led us to conceive an innovative method to measure bile acid transport in live animals using a combination of proton (1H) and fluorine (19F) magnetic resonance imaging (MRI). Novel tracers for fluorine (19F)-based live animal MRI were created and tested, both in vitro and in vivo. Strengths of this approach include the lack of exposure to ionizing radiation and translational potential for clinical research and practice.
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PMID:Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport. 2792 65