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Article ; Online: Effect of ASP8062 on morphine self-administration and morphine-induced respiratory suppression in monkeys.

Akuzawa, Shinobu / Irie, Megumi / Kanki, Masayuki / Shirakawa, Takafumi / Sato, Yuichiro

2023 Volume 151, Issue 4, Page(s) 171–176

Abstract: ASP8062 is an orally available ... ...

Abstract	ASP8062 is an orally available GABA
MeSH term(s)	Animals ; Morphine ; Macaca fascicularis ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Dose-Response Relationship, Drug
Chemical Substances	Morphine (76I7G6D29C) ; ASP8062
Language	English
Publishing date	2023-02-15
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2104264-0
ISSN	1347-8648 ; 1347-8613
ISSN (online)	1347-8648
ISSN	1347-8613
DOI	10.1016/j.jphs.2023.02.003
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Zs.A 237: Show issues

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Article ; Online: Effects of (+)-bicuculline, a GABAa receptor antagonist, on auditory steady state response in free-moving rats.

Yamazaki, Mayako / Honda, Sokichi / Tamaki, Keisuke / Irie, Megumi / Mihara, Takuma

PloS one

2020 Volume 15, Issue 7, Page(s) e0236363

Abstract: Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as ... ...

Abstract	Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as for their capacity to generate synchronous activity in both human and animal models. Furthermore, abnormal gamma oscillations on ASSR are typically observed in patients with schizophrenia (SZ). Changes in neural synchrony may reflect aberrations in cortical gamma-aminobutyric acid (GABA) neurotransmission. However, GABA's impact and effects related to ASSR are still unclear. Here, we examined the effect of a GABAa receptor antagonist, (+)-bicuculline, on ASSR in free-moving rats. (+)-Bicuculline (1, 2 and 4 mg/kg, sc) markedly and dose-dependently reduced ASSR signals, consistent with current hypotheses. In particular, (+)-bicuculline significantly reduced event-related spectral perturbations (ERSPs) at 2 and 4 mg/kg between 10 and 30 minutes post-dose. Further, bicuculline (2 and 4 mg/kg) significantly and dose-dependently increased baseline gamma power. Furthermore, the occurrence of convulsions was consistent with the drug's pharmacokinetics. For example, high doses of (+)-bicuculline such as those greater than 880 ng/g in the brain induced convulsion. Additionally, time-dependent changes in ERSP with (+)-bicuculline were observed in accordance with drug concentration. This study partially unraveled the contribution of GABAa receptor signals to the generation of ASSR.
MeSH term(s)	Animals ; Auditory Cortex/drug effects ; Bicuculline/administration & dosage ; Bicuculline/pharmacokinetics ; Convulsants/administration & dosage ; Convulsants/pharmacokinetics ; Evoked Potentials, Auditory/drug effects ; GABA-A Receptor Antagonists/administration & dosage ; GABA-A Receptor Antagonists/pharmacokinetics ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A/metabolism ; Schizophrenia/physiopathology ; Synaptic Transmission/drug effects
Chemical Substances	Convulsants ; GABA-A Receptor Antagonists ; Receptors, GABA-A ; Bicuculline (Y37615DVKC)
Language	English
Publishing date	2020-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0236363
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Article ; Online: AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain.

Murai, Nobuhito / Takeshita, Nobuaki / Nishigaki, Fusako / Irie, Megumi / Tamura, Seiji / Aoki, Toshiaki / Matsuoka, Nobuya

Neurological research

2015 Volume 37, Issue 6, Page(s) 525–530

Abstract: Objectives: The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the ... ...

Abstract	Objectives: The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the analgesic effects of AS1069562 in rat models of inflammatory and noninflammatory nociceptive pain. Methods: Adjuvant-induced arthritis (AIA) and bradykinin-induced knee joint pain were used as rat models of inflammatory pain. The chronic phase of monoiodoacetate-induced arthritis (MIA) was used as a rat model of noninflammatory pain. Analgesic effects were evaluated by weight-bearing deficit in the AIA and MIA models and by pain response in the bradykinin-induced knee joint pain model. Results: In the AIA model and the bradykinin-induced knee joint pain model, AS1069562 significantly ameliorated the pain-related behavior of weight-bearing deficit and the pain response, respectively. AS1069562 also significantly improved the pain-related behavior of weight-bearing deficit in the chronic phase of the MIA model. Further, following monoiodoacetate injection, repeated administration of AS1069562 or duloxetine significantly improved weight-bearing deficit in the MIA model. Interestingly, the analgesic effect of AS1069562 was sustained for 24 hours after the last administration, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the analgesic effect of duloxetine did not continue after treatment discontinuation. Discussion: AS1069562 exerts analgesic effects on inflammatory and noninflammatory nociceptive pain in rat models of arthritis pain, and repeated administration of AS1069562 exerts a more persistent analgesic effect on arthritis pain than duloxetine. These findings suggest that AS1069562 has an attractive analgesic profile for the treatment of nociceptive pain.
MeSH term(s)	Analgesics/blood ; Analgesics/pharmacology ; Animals ; Arthralgia/drug therapy ; Arthralgia/physiopathology ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/physiopathology ; Bradykinin ; Chronic Disease ; Disease Models, Animal ; Duloxetine Hydrochloride/pharmacology ; Female ; Male ; Morpholines/blood ; Morpholines/pharmacology ; Nociceptive Pain/drug therapy ; Nociceptive Pain/physiopathology ; Pain Measurement ; Rats, Inbred Lew ; Rats, Sprague-Dawley ; Time Factors
Chemical Substances	Analgesics ; Morpholines ; indeloxazine (834M09R1KM) ; Duloxetine Hydrochloride (9044SC542W) ; Bradykinin (S8TIM42R2W)
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	424428-x
ISSN	1743-1328 ; 0161-6412
ISSN (online)	1743-1328
ISSN	0161-6412
DOI	10.1179/1743132815Y.0000000007
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Zs.A 1491: Show issues

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Article ; Online: Case report of extensive metabolism by aldehyde oxidase in humans: pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans.

Akabane, Takafumi / Tanaka, Kohichiro / Irie, Megumi / Terashita, Shigeyuki / Teramura, Toshio

Xenobiotica; the fate of foreign compounds in biological systems

2011 Volume 41, Issue 5, Page(s) 372–384

Abstract: We describe the preclinical and clinical pharmacokinetic profiles of FK3453 [6-(2-amino-4-phenylpyrimidin-5-yl)-2-isopropylpyridazin-3(2H)-one] and the mechanism responsible for poor oral exposure of FK3453 in humans. FK3453 showed favourable profiles in ...

Abstract	We describe the preclinical and clinical pharmacokinetic profiles of FK3453 [6-(2-amino-4-phenylpyrimidin-5-yl)-2-isopropylpyridazin-3(2H)-one] and the mechanism responsible for poor oral exposure of FK3453 in humans. FK3453 showed favourable profiles in preclinical pharmacokinetic studies, including satisfactory absolute bioavailability and total body clearance in animals (30.5%-41.4%, 54.7%-68.2%, and 71.3%-93.4% and 10.8-17.6, 1.9-17.1, and 5.0 mL/min/kg in male rats, female rats, and dogs, respectively), and good metabolic stability in liver microsomes (42.3, 14.5, and 1.1 mL/min/kg in male rats, dogs, and humans, respectively). However, despite these promising preclinical findings, plasma concentrations of FK3453 in humans were extremely low, with the oxidative metabolite of the aminopyrimidine moiety (M4) identified as a major metabolite. Given that aldehyde oxidase (AO) and xanthine oxidase (XO) were presumed to be the enzymes responsible for M4 formation, we investigated the mechanism of M4 formation using human liver subcellular fractions. M4 was detected in the incubation mixture with S9 and cytosol but not with microsomes, and M4 formation was inhibited by AO inhibitors (menadione, isovanillin) but not by cytochrome P-450 inhibitor (1-aminobenzotiazole) or XO inhibitor (allopurinol). These results suggest M4 formation is catalyzed by AO, and therefore, its poor exposure in humans was attributed to extensive AO metabolism.
MeSH term(s)	Administration, Oral ; Adult ; Aldehyde Oxidase/metabolism ; Animals ; Biological Availability ; Chromatography, High Pressure Liquid ; Cytosol/enzymology ; Dogs ; Female ; Humans ; Injections, Intravenous ; Liver/metabolism ; Male ; Metabolic Networks and Pathways ; Metabolome ; Protein Binding ; Pyridazines/administration & dosage ; Pyridazines/metabolism ; Pyridazines/pharmacokinetics ; Pyrimidines/administration & dosage ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Pyrimidines/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Subcellular Fractions/metabolism ; Time Factors ; Young Adult
Chemical Substances	FK3453 ; Pyridazines ; Pyrimidines ; Aldehyde Oxidase (EC 1.2.3.1)
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.3109/00498254.2010.549970
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Zs.A 782: Show issues

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Article: Genetic variant Arg57His in human H+/peptide cotransporter 2 causes a complete loss of transport function.

Terada, Tomohiro / Irie, Megumi / Okuda, Masahiro / Inui, Ken-ichi

Biochemical and biophysical research communications

2004 Volume 316, Issue 2, Page(s) 416–420

Abstract: We evaluated the functional consequences of genetic variations in human H(+)/peptide cotransporter 2 (hPEPT2, SLC15A2) resulting in the amino acid changes Arg57His (R57H) and Pro409Ser (P409S). The transport activity of variant R57H was completely ... ...

Abstract	We evaluated the functional consequences of genetic variations in human H(+)/peptide cotransporter 2 (hPEPT2, SLC15A2) resulting in the amino acid changes Arg57His (R57H) and Pro409Ser (P409S). The transport activity of variant R57H was completely abolished, whereas that of variant P409S was comparable with that of wild-type hPEPT2 at pH 5.0-8.0. R57H variant protein was detected in the crude membranes of transiently expressed HEK293 cells by Western blot analysis. The expression of the R57H variant at the plasma membrane was confirmed by indirect immunofluorescence in Xenopus oocytes, suggesting that the loss of transport function of hPEPT2 R57H was not due to a change in membrane protein expression. This is the first demonstration of a functional impairment of the SLC15A family induced by a single nucleotide polymorphism.
MeSH term(s)	Amino Acid Substitution ; Animals ; Arginine/genetics ; Biological Transport ; Cell Line ; Cell Membrane/enzymology ; Cells, Cultured ; Dipeptides/metabolism ; Histidine/genetics ; Humans ; Hydrogen-Ion Concentration ; Oocytes/metabolism ; Polymorphism, Single Nucleotide ; Symporters/genetics ; Symporters/metabolism ; Xenopus
Chemical Substances	Dipeptides ; Symporters ; hydrogen-coupled oligopeptide transporter PepT2 ; glycylsarcosine (29816-01-1) ; Histidine (4QD397987E) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2004-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2004.02.063
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Zs.A 116: Show issues

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Article: Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2.

Irie, Megumi / Terada, Tomohiro / Okuda, Masahiro / Inui, Ken-Ichi

Pflugers Archiv : European journal of physiology

2004 Volume 449, Issue 2, Page(s) 186–194

Abstract: Small peptides and some pharmacologically active compounds are absorbed from the small intestine by the apical H(+)-coupled peptide transporter 1 (PEPT1) and the basolateral peptide transporter. Here we investigated the efflux properties of the ... ...

Abstract	Small peptides and some pharmacologically active compounds are absorbed from the small intestine by the apical H(+)-coupled peptide transporter 1 (PEPT1) and the basolateral peptide transporter. Here we investigated the efflux properties of the basolateral peptide transporter in Caco-2 cells using two strategies, efflux measurements and a kinetic analysis of transepithelial transport of glycylsarcosine (Gly-Sar). [(14)C]Gly-Sar efflux through the basolateral membrane was not affected significantly by the external pH. Both approaches revealed that the basolateral peptide transporter was saturable in the efflux direction, and that the affinity was lower than that in the influx direction. For two peptide-like drugs, there was no difference in substrate recognition by the basolateral peptide transporter between the two sides of the membrane. Using the kinetic parameters of PEPT1 and the basolateral peptide transporter, a computational model of Gly-Sar transport in Caco-2 cells was constructed. The simulation fitted the experimental data well. Our findings suggested that substrate affinity of the basolateral peptide transporter is apparently asymmetric, but pH-dependence and substrate specificity are symmetric for the two directions of transport. The behaviour of Gly-Sar in Caco-2 cells could be predicted by a mathematical model describing the peptide transporters.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Biological Transport/drug effects ; Biological Transport/physiology ; Caco-2 Cells ; Carbon Radioisotopes ; Cell Polarity/physiology ; Cephalosporins/pharmacology ; Computer Simulation ; Cyclacillin/pharmacology ; Dipeptides/pharmacokinetics ; Humans ; Hydrogen-Ion Concentration ; Intestinal Mucosa/cytology ; Intestinal Mucosa/metabolism ; Kinetics ; Linear Models ; Membrane Transport Proteins/metabolism ; Models, Biological
Chemical Substances	Anti-Bacterial Agents ; Carbon Radioisotopes ; Cephalosporins ; Dipeptides ; Membrane Transport Proteins ; glycylsarcosine (29816-01-1) ; Cyclacillin (72ZJ154X86) ; peptide permease (97599-47-8) ; ceftibuten (IW71N46B4Y)
Language	English
Publishing date	2004-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-004-1326-x
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Article ; Online: Two models for weight gain and hyperphagia as side effects of atypical antipsychotics in male rats: validation with olanzapine and ziprasidone.

Shobo, Miwako / Yamada, Hiroshi / Mihara, Takuma / Kondo, Yuji / Irie, Megumi / Harada, Katsuya / Ni, Keni / Matsuoka, Nobuya / Kayama, Yukihiko

Behavioural brain research

2011 Volume 216, Issue 2, Page(s) 561–568

Abstract: Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight ... ...

Abstract	Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.
MeSH term(s)	Animals ; Antipsychotic Agents/administration & dosage ; Antipsychotic Agents/adverse effects ; Benzodiazepines/administration & dosage ; Benzodiazepines/adverse effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Feeding Behavior/drug effects ; Hyperphagia/chemically induced ; Male ; Piperazines/administration & dosage ; Piperazines/adverse effects ; Rats ; Rats, Sprague-Dawley ; Thiazoles/administration & dosage ; Thiazoles/adverse effects ; Weight Gain/drug effects
Chemical Substances	Antipsychotic Agents ; Piperazines ; Thiazoles ; Benzodiazepines (12794-10-4) ; ziprasidone (6UKA5VEJ6X) ; olanzapine (N7U69T4SZR)
Language	English
Publishing date	2011-01-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	449927-x
ISSN	1872-7549 ; 0166-4328
ISSN (online)	1872-7549
ISSN	0166-4328
DOI	10.1016/j.bbr.2010.08.046
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Zs.A 1599: Show issues

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Article: Prediction of glycylsarcosine transport in Caco-2 cell lines expressing PEPT1 at different levels.

Irie, Megumi / Terada, Tomohiro / Tsuda, Masahiro / Katsura, Toshiya / Inui, Ken-Ichi

Pflugers Archiv : European journal of physiology

2006 Volume 452, Issue 1, Page(s) 64–70

Abstract: H(+)-coupled peptide transporter 1 (PEPT1) and the basolateral peptide transporter mediate the absorption of small peptides and peptide-like drugs in the small intestine. Recently, we constructed a mathematical model to simulate glycylsarcosine (Gly-Sar) ...

Abstract	H(+)-coupled peptide transporter 1 (PEPT1) and the basolateral peptide transporter mediate the absorption of small peptides and peptide-like drugs in the small intestine. Recently, we constructed a mathematical model to simulate glycylsarcosine (Gly-Sar) transport in Caco-2 cells. In this study, we attempted to adjust our model to a change in the expression level of PEPT1. To obtain cell lines expressing PEPT1 at different levels, recloning of Caco-2 cells was performed, and nine clones were isolated. Compared with parental cells, clones 1 and 9 exhibited the lowest and the highest levels of [(14)C]Gly-Sar uptake from the apical side, respectively, whereas activities of the basolateral peptide transporter were comparable. Kinetic analysis demonstrated that the difference in the activity of PEPT1 was accounted by variations in V (max). Moreover, PEPT1 mRNA level was positively related to the activity of [(14)C]Gly-Sar uptake (r=0.55). Based on these findings, the V (max) value of PEPT1 was defined as a variable using the amount of PEPT1 mRNA as an index of the expression level. With this improved model, Gly-Sar transport in clones 1 and 9 was well-predicted, suggesting that our model can simulate Gly-Sar transport in cells expressing PEPT1 at different levels.
MeSH term(s)	Biological Transport/physiology ; Caco-2 Cells ; Carbon Radioisotopes ; Computer Simulation ; Dipeptides/metabolism ; Epithelium/metabolism ; Gene Expression ; Humans ; Kinetics ; Models, Biological ; Peptide Transporter 1 ; RNA, Messenger/metabolism ; Symporters/metabolism
Chemical Substances	Carbon Radioisotopes ; Dipeptides ; Peptide Transporter 1 ; RNA, Messenger ; Symporters ; glycylsarcosine (29816-01-1)
Language	English
Publishing date	2006-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-005-0005-x
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Article: Computational modelling of H+-coupled peptide transport via human PEPT1.

Irie, Megumi / Terada, Tomohiro / Katsura, Toshiya / Matsuoka, Satoshi / Inui, Ken-ichi

The Journal of physiology

2005 Volume 565, Issue Pt 2, Page(s) 429–439

Abstract: H+-coupled peptide transporter 1 (PEPT1) mediates the transport of small peptides and peptide-like drugs in a pH- and voltage-dependent manner. Here, we investigated the transport mechanisms of PEPT1 for neutral and charged substrates by experimental ... ...

Abstract	H+-coupled peptide transporter 1 (PEPT1) mediates the transport of small peptides and peptide-like drugs in a pH- and voltage-dependent manner. Here, we investigated the transport mechanisms of PEPT1 for neutral and charged substrates by experimental studies and computational simulation. Uptake studies revealed that the Michaelis-Menten constant (Km) of glycylsarcosine (Gly-Sar), a neutral substrate, decreased with a fall in pH from 7.4 to 5.5, but at pH 5.0, the Km increased again. In contrast, the Km value of an anionic substrate, ceftibuten, declined steadily with decreasing pH. Based on these findings and information from the literature, we hypothesized the transport mechanisms in which (1) H+ binds to not only the H+-binding site, but also the substrate-binding site; and (2) H+ at the substrate-binding site inhibits the interaction of neutral and cationic substrates, but is necessary for that of anionic substrates. To validate these hypotheses, a computational model was constructed and various properties of substrate transport by PEPT1 were simulated. Our model reproduced the voltage dependence, hyperbolic saturation and bell-shaped pH-profile of Gly-Sar transport. Moreover, the various transport properties of negatively and positively charged substrates were also reconstructed. These findings indicated that the inferred mechanisms are able to sufficiently interpret the transport of both neutral and charged substrates by PEPT1.
MeSH term(s)	Anions/metabolism ; Caco-2 Cells ; Cations/metabolism ; Cephalosporins/pharmacokinetics ; Computer Simulation ; Dipeptides/pharmacokinetics ; Electrochemistry ; Humans ; Hydrogen-Ion Concentration ; Membrane Potentials/physiology ; Models, Chemical ; Peptide Transporter 1 ; Peptides/metabolism ; Protein Binding ; Protons ; Symporters/chemistry ; Symporters/metabolism
Chemical Substances	Anions ; Cations ; Cephalosporins ; Dipeptides ; Peptide Transporter 1 ; Peptides ; Protons ; SLC15A1 protein, human ; Symporters ; glycylsarcosine (29816-01-1) ; ceftibuten (IW71N46B4Y)
Language	English
Publishing date	2005-06-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/jphysiol.2005.084582
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Uc I Zs.65: Show issues

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Article: Diurnal rhythm of H+-peptide cotransporter in rat small intestine.

Pan, Xiaoyue / Terada, Tomohiro / Irie, Megumi / Saito, Hideyuki / Inui, Ken-Ichi

American journal of physiology. Gastrointestinal and liver physiology

2002 Volume 283, Issue 1, Page(s) G57–64

Abstract: In mammals, most physiological, biochemical, and behavioral processes show a circadian rhythm. In the present study, we examined the diurnal rhythm of the H+-peptide cotransporter (PEPT1), which transports small peptides and peptide-like drugs in the ... ...

Abstract	In mammals, most physiological, biochemical, and behavioral processes show a circadian rhythm. In the present study, we examined the diurnal rhythm of the H+-peptide cotransporter (PEPT1), which transports small peptides and peptide-like drugs in the small intestine and kidney, using rats maintained in a 12-h photoperiod with free access to chow. The transport of [14C]glycylsarcosine (Gly-Sar), a typical substrate for PEPT1 by in situ intestinal loop and everted intestine, was greater in the dark phase than the light phase. PEPT1 protein and mRNA levels varied significantly, with a maximum at 2000 and minimum at 800. Similar functional and expressional diurnal variations were observed in the intestinal Na+-glucose cotransporter (SGLT1). In contrast, renal PEPT1 and SGLT1 showed little diurnal rhythmicity in protein and mRNA expression. These findings indicate that the intestinal PEPT1 undergoes diurnal regulation in its activity and expression, and this could affect the intestinal absorption of dietary protein.
MeSH term(s)	Absorption ; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Circadian Rhythm ; Dipeptides/pharmacokinetics ; Duodenum/metabolism ; In Vitro Techniques ; Kidney/metabolism ; Male ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Monosaccharide Transport Proteins/genetics ; Monosaccharide Transport Proteins/metabolism ; Peptide Transporter 1 ; Photoperiod ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Sodium-Glucose Transporter 1 ; Symporters/genetics ; Symporters/metabolism
Chemical Substances	Carrier Proteins ; Dipeptides ; Membrane Glycoproteins ; Monosaccharide Transport Proteins ; Peptide Transporter 1 ; RNA, Messenger ; Slc15a1 protein, rat ; Slc5a1 protein, rat ; Sodium-Glucose Transporter 1 ; Symporters ; hydrogen-coupled oligopeptide transporter PepT2 ; glycylsarcosine (29816-01-1)
Language	English
Publishing date	2002-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.00545.2001
Database	MEDical Literature Analysis and Retrieval System OnLINE

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