Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Kim, C S; Roe, Charles R.; Mann, J.D.; Breese, George R.

doi:10.1111/j.1471-4159.1992.tb11370.x

Cited by 14 publications

(8 citation statements)

References 31 publications

(28 reference statements)

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“…Rat organic anion transporter 3-mediated [ 3 H]HVA transport was also significantly inhibited by probenecid and octanoic acid. This result is in good agreement with previous reports showing that the HVA concentration in the brain was increased by systemic administration of probenecid or octanoic acid (Emanuelsson et al, 1987;Kim et al, 1992). These results A and B) or doubly (C and D) labeled rat brain sections.…”

Section: Discussionsupporting

confidence: 93%

“…The HVA concentration in the CSF is elevated in patients with Reye's syndrome (Shaywitz et al, 1979). In rats, after intraperitoneal administration of octanoic acid, the concentrations of HVA and 5-HIAA in the caudate nucleus were increased to 154% and 150%, respectively (Kim et al, 1992). These observations suggest that increased plasma and brain levels of octanoic acid could induce elevation of brain HVA levels in patients.…”

Section: Figmentioning

confidence: 86%

“…The CNS is believed to possess an efflux system that prevents the accumulation of HVA in the brain, because HVA concentration in the brain was increased when probenecid or octanoic acid (a fatty acid that is increased in the blood of patients with Reye's syndrome and mediumchain acyl-CoA dehydrogenase deficiency), was administered peripherally (Emanuelsson et al, 1987;Kim et al, 1992). Moreover, microdialysis findings suggested that the brain-to-blood efflux transport rate of HVA is faster than the blood-to-brain HVA influx rate across the blood-brain barrier (BBB) (Morrison et al, 1999).…”

mentioning

confidence: 99%

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Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells

Mori¹,

Takanaga

Ohtsuki

et al. 2003

J Cereb Blood Flow Metab

140

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The mechanism that removes homovanillic acid (HVA), an end metabolite of dopamine, from the brain is still poorly understood. The purpose of this study is to identify and characterize the brain-to-blood HVA efflux transporter at the rat blood-brain barrier (BBB). Using the Brain Efflux Index method, the apparent in vivo efflux rate constant of [3H]HVA from the brain, k(eff), was determined to be 1.69 x 10(-2) minute(-1). This elimination was significantly inhibited by para-aminohippuric acid (PAH), benzylpenicillin, indoxyl sulfate, and cimetidine, suggesting the involvement of rat organic anion transporter 3 (rOAT3). rOAT3-expressing oocytes exhibited [3H]HVA uptake (K(m) = 274 micromol/L), which was inhibited by several organic anions, such as PAH, indoxyl sulfate, octanoic acid, and metabolites of monoamine neurotransmitters. Neurotransmitters themselves did not affect the uptake. Furthermore, immunohistochemical analysis suggested that rOAT3 is localized at the abluminal membrane of brain capillary endothelial cells. These results provide the first evidence that rOAT3 is expressed at the abluminal membrane of the rat BBB and is involved in the brain-to-blood transport of HVA. This HVA efflux transport system is likely to play an important role in controlling the level of HVA in the CNS.

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Section: Discussionsupporting

confidence: 93%

Section: Figmentioning

confidence: 86%

mentioning

confidence: 99%

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Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells

Mori¹,

Takanaga

Ohtsuki

et al. 2003

J Cereb Blood Flow Metab

140

View full text Add to dashboard Cite

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“…The HVA concentration in blood and urine is widely used as an indicator of dopaminergic neuronal activity in the brain. Previous studies have indicated that the HVA concentration in the brain is increased when probenecid or octanoic acid is administered peripherally (69,70). These results suggested that a probenecid-and octanoic acid-sensitive transporter(s) mediates the efflux transport of HVA at the BBB.…”

Section: Brain-to-blood Efflux Transporters As a Physiological And Phmentioning

confidence: 63%

Contribution of Carrier-Mediated Transport Systems to the Blood–Brain Barrier as a Supporting and Protecting Interface for the Brain; Importance for CNS Drug Discovery and Development

2007

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The blood-brain barrier (BBB) forms an interface between the circulating blood and the brain and possesses various carrier-mediated transport systems for small molecules to support and protect CNS function. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx transporters are expected to have high permeability across the BBB. On the other hand, efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these transporters are expected to show low BBB permeability and low distribution to the brain. Despite recent progress, the transport mechanisms at the BBB have not been fully clarified yet, especially in humans. However, an understanding of the human BBB transport system is critical, because species differences mean that it can be difficult to extrapolate data obtained in experimental animals during drug development to humans. Recent progress in methodologies is allowing us to address this issue. Positron emission tomography can be used to evaluate the activity of human BBB transport systems in vivo. Proteomic studies may also provide important insights into human BBB function. Construction of a human BBB transporter atlas would be a most important advance from the viewpoint of CNS drug discovery and drug delivery to the brain.

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“…43,44) Brain microdialysis studies have suggested that the brain-to-blood efflux transport rate of HVA is faster than the blood-to-brain HVA influx rate across the BBB. 45) These results suggest that a probenecid-and octanoic acid-sensitive transporter(s) mediates the efflux transport of HVA at the BBB.…”

mentioning

confidence: 99%

New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System

Ohtsuki

2004

Biological & Pharmaceutical Bulletin

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The blood-brain barrier (BBB) is formed by complex tight-junctions of the brain capillary endothelial cells (BCECs) and expresses various transport systems. These characteristics of the BBB make it possible to control selective transport across the BBB and to limit the non-selective brain distribution of drugs. Since understanding the mechanism of BBB transport is important for improving the BBB permeability of CNS-acting drugs, the molecular mechanism of the BBB transport has been analyzed mainly with respect to drug transport. At first, blood-to-brain influx transport was regarded as a system for transporting drugs and nutrients to the brain. This resulted in the discovery of transport systems for glucose and amino acids. 1) Subsequently, the importance of efflux transport at the BBB has been recognized after finding that P-glycoprotein (P-gp) is involved in the efflux transport of xenobiotics.2,3) Due to these studies, the BBB is now accepted as a complex transport system which is an important determinant of drug distribution to the brain.In addition to the drug permeability aspects, the physiological function of the BBB is important in the central nervous system (CNS). To date, the BBB transport system has been shown to supply nutrients, such as glucose, lactate, amino acids and nucleotides, to the brain. However, it is conceivable that the BBB have many other physiological functions involving regulation of the CNS milieu. For instance, the brain is a highly energy-consuming tissue and produces various metabolites. In particular, metabolism is essential for the inactivation of neurotransmitters after their secretion from the pre-synapses, as well as re-uptake. The metabolites produced in the brain must be removed in order to maintaine proper neural function. Therefore, the BBB can be thought to act as a clearance system to remove various metabolites from the CNS.Clarifying the physiological role of the BBB is also necessary to understand the role of the BBB in CNS disorders. This is because an alteration in BBB functions may result in a change in CNS conditions leading to CNS disorders. Furthermore, analyzing the BBB functions from a different point of view could result in the discovery of a new transport system that is involved in drug permeability. In this review, I shall introduce the recent advances in research into the molecular basis of BBB transport, focusing on its physiological functions.The BBB Supplies Creation to the Brain The brain consumes 18% of total body energy, while its weight is only 2% of the total body weight. The brain cannot store glucose for energy synthesis, and the BBB plays a crucial role in glucose supply to the brain by expressing glucose transporter 1 (GLUT1) (Fig. 1). 4) Besides energy synthesis, an energystoring system is necessary for maintain energy homeostasis in high energy-consuming tissues. We have shown that the BBB also plays an important role in the energy storing process (Fig. 1). 5)Creatine plays a key role in this energy-storing process. The phosphate-bound energy...

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Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Cited by 14 publications

References 31 publications

Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells

Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells

Contribution of Carrier-Mediated Transport Systems to the Blood–Brain Barrier as a Supporting and Protecting Interface for the Brain; Importance for CNS Drug Discovery and Development

New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System

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