Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606 - 8507, Japan
![]() |
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.
kidney; intestinal absorption; brush-border membranes
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
DIETARY PROTEIN
UNDERGOES a series of degradative steps, resulting in a mixture
of free amino acids and small peptides. Numerous studies have shown
that absorption of the products of protein digestion in the small
intestine occurs primarily in the form of small peptides rather than
amino acids (1, 17). Cellular uptake of small peptides
(di- and tripeptides) is mediated by H+-coupled peptide
transporter (PEPT1) localized at the brush-border membranes of
intestinal epithelial cells (17, 20). In the kidney, two
isoforms of peptide transporters (PEPT1 and PEPT2) are expressed and
play a significant role in conserving peptide-bound amino nitrogen
(9, 20). On the basis of the nutritional importance of
peptides, enteral and parenteral solutions of short-chain peptides have
been used in clinical settings (13). Thus the clinical relevance of PEPT1 and PEPT2 has received increasing attention in
recent years. Furthermore, both peptide transporters can transport several pharmacologically active drugs, such as oral -lactam antibiotics and the anticancer agent bestatin, and affect their intestinal absorption and therapeutic efficacy (17). All
of these findings suggest that the intestinal and renal peptide
transporters PEPT1 and PEPT2 play important physiological,
pharmacological, and clinical roles.
In mammals, most physiological, biochemical, and behavioral processes vary in a periodic manner with respect to time of day. When amino acids, rather than small peptides, were considered to be important as nutritional elements for protein homeostasis, there were a number of reports on the circadian rhythm of amino acid metabolism, such as plasma levels of amino acids (11), amino acid transport and metabolism in the liver (4, 45), and intestinal absorption of L-histidine (12). These studies demonstrated that the highest values or activities were observed in dark phases, and these diurnal changes might be assumed to occur in nocturnal animals feeding mainly at night. However, there have been few reports on the diurnal rhythms for transport and metabolism of small peptides, although the physiological and clinical significance of small peptides has been recognized.
In the present study, we focused on the diurnal rhythms of intestinal absorption of small peptides and its molecular mechanism. To achieve this, diurnal changes of [14C]glycylsarcosine (Gly-Sar) transport in the small intestine were examined. Expressional changes of PEPT1 mRNA and protein in the small intestine were also investigated. Furthermore, we compared the expressional changes of intestinal PEPT1 to those of renal PEPT1, to examine the tissue specificity of circadian rhythms. Diurnal rhythms of the Na+-glucose cotransporter (SGLT1) in the small intestine and kidney were also examined to compare with those of PEPT1, because the intestinal SGLT1 was reported to show a circadian rhythm (30, 42).
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. Animal experiments were performed in accordance with the Guidelines for Animal Experiments of Kyoto University. Male Wistar rats (160-180 g) were housed in an air-conditioned room at 22 ± 0.5°C with a 12-h lighting schedule (800-2000). Animals were kept for at least 1 wk before the initiation of any experiments and were allowed free access to water and standard laboratory chow.
Materials.
[14C]Gly-Sar (1.78 GBq/mmol) was obtained from Daiichi
Pure Chemicals (Ibaraki, Japan).
[14C]methyl--D-[U-14C]glucopyranoside
(
MG); (9.66 GBq/mmol) was supplied by Moravek Biochemicals (Brea,
CA). Gly-Sar was purchased from Sigma (St. Louis, MO). All other
chemicals used were of the highest purity available.
In situ loop technique.
We examined [14C]Gly-Sar transport by the in situ loop
technique at 1200 and 2400. A cannula with a polyethylene tube was
inserted in the portal artery. A duodenum loop 10 cm in length was
prepared, and then [14C]Gly-Sar (40 nmol · ml1 · kg body wt
1)
was introduced into the loop with a microsyringe. Blood was withdrawn
from the portal artery at designated times. Blood samples were
centrifuged for 2 min at 14,000 g, and 50 µl of plasma was solubilized in 0.5 ml of NCS II (Amersham Pharmacia Biotech, Uppsala, Sweden). Radioactivity was determined in 5 ml of ACS II
(Amersham Pharmacia Biotech) by liquid scintillation counting.
Preparation of intestinal segments and uptake experiments.
Rats were killed at different times during a 24-h period (400, 800, 1200, 1600, 2000, and 2400), and the intestinal segments for the uptake
experiments were quickly prepared according to a previous report
(24) with some modifications. Isolated duodenum was
everted, divided into small segments 5-10 mm in length, and fixed
over polyethylene tubes with an outer diameter of 4 mm. Everted
intestinal segments were preincubated with incubation medium under an
atmosphere of 100% oxygen. The composition of the incubation medium
was as follows (in mM): 129 NaCl, 5.1 KCl, 1.4 CaCl2, 1.3 NaH2PO4, and 1.3 Na2HPO4 (pH 6.0). After preincubation, each
intestinal segment was placed in 1 ml of incubation medium containing
[14C]Gly-Sar (20 µM) or MG (100 µM). The uptake
experiments were carried out at 37°C an atmosphere of 100% oxygen.
After incubation for 3 min, each segment was rapidly washed with
ice-cold incubation medium, blotted on filter paper, weighed, and
solubilized in 0.5 ml of NCS II. Radioactivity was then determined in 5 ml of ACS II by liquid scintillation counting.
Antibodies and Western blot analysis. Rabbit anti-PEPT1 antibody was raised against the 15 COOH-terminal amino acids of rat PEPT1 (31). Rabbit anti-PEPT2 antibody was raised against synthetic peptides corresponding to amino acids 697-710 of rat PEPT2 (39). Rabbit anti-SGLT1 antibody (a gift of M. Kasahara) was raised against synthetic peptides corresponding to amino acids 564-575 of rabbit intestinal SGLT1 (40). Goat antivillin polyclonal IgG was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). While the animals were under anesthesia, the duodenum and kidney were removed at specified times. The duodenum was flushed with cold PBS, and the mucosa was scraped. The kidney was decapsulated, and slices of renal cortex were prepared with a Stadie-Riggs microtome. A portion of the mucosa and renal slices were rapidly frozen in liquid nitrogen for later preparation of brush-border membranes and total RNA. Brush-border membranes from rat small intestine and kidney cortex were prepared as described previously (16, 29). The membrane fractions were separated by SDS-PAGE and analyzed by Western blotting with each antibody as reported (23, 26, 31, 39). Relative amounts of band in each reaction were determined densitometrically using Image 1.61 (National Institutes of Health, Bethesda, MD).
Immunohistochemistry.
Immunohistochemistry was performed as described previously (26,
27). Briefly, fresh specimens were cut transversely, and the
lumens were washed with PBS. Samples were embedded in optimal cutting
temperature compound (Sakura Finetechnical, Tokyo, Japan), rapidly
frozen in liquid nitrogen, and stored at 80°C until used. Frozen
sections were cut with a cryostat (5-µm thick), mounted on glass
slides, fixed in ethanol for 15 min at
15°C, and washed with PBS at
room temperature. The sections were then covered with 5% normal goat
serum for 10 min and incubated with anti-PEPT1 antibody at a dilution
of 1:250 for 1 h. After being washed with PBS, the sections were
next incubated with 3 µg/ml of Cy3-labeled donkey anti-rabbit IgG
(CALTAG Laboratory, San Francisco, CA) for 1 h and then washed
with PBS. These sections were examined with a BX-50-FLA fluorescence
microscope (Olympus, Tokyo, Japan) at a magnification of ×100. Images
were captured with a DP-50 charge-coupled device (CCD) camera (Olympus)
using Studio Lite software (Olympus). After the fluorescence images had
been captured, they were processed and analyzed with IP Lab Spectrum
image analysis software (Signal Analytics, Vienna, VA).
Northern blot analysis.
Total RNA was extracted using the guanidine isothiocyanate method
(7). Each amount of total RNA was electrophoresed in 1%
denaturing agarose gel containing formaldehyde and transferred onto
nylon membranes. The quality of the RNA was assessed by ethidium bromide staining. After transfer, blots were hybridized at high stringency [50% formamide, 5× sodium chloride-sodium phosphate-EDTA (SSPE) (1× SSPE is 0.15 M NaCl, 10 mM NaH2PO4, and 1 mM
EDTA), 5× Denhardt's solution, 0.2% SDS, and 10 µg/ml herring
sperm DNA at 42°C] with PEPT1, PEPT2, SGLT1 and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA fragments labeled
with [-32P]dCTP as probes. Each probe was already
prepared, sequenced, and used for Northern blot analysis (31, 32,
41). After being hybridized, the blots were washed several times
in 2× SSC (1× SSC is 0.15 M NaCl, and 15 mM sodium citrate, pH
7.0)/0.1% SDS at room temperature. Dried membranes were exposed to the
imaging plates of a Fujix Bio-Imaging Analyzer BAS 2000 II (Fuji Photo Film).
Data analysis. Data were analyzed statistically by the nonpaired t-test or one-way ANOVA followed by Fisher's test when multiple comparisons were needed.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
[14C]Gly-Sar absorption by in situ intestinal loops
at 1200 and 2400.
First, we examined the intestinal absorption of
[14C]Gly-Sar by in situ intestinal loops in the middle of
the light phase (1200) and the middle of the dark phase (2400). Figure
1 shows the mean portal vein
concentrations after intraduodenal administration of
[14C]Gly-Sar. The initial absorption rate of
[14C]Gly-Sar was significantly faster at 2400 than at
1200.
|
Uptake studies by rat intestinal segments.
We then examined the uptake of [14C]Gly-Sar by intestinal
segments at different times during a 24-h period. MG was also
measured. Accumulation of both substrates into intestinal segments
increased linearly with time up to at least 3 min (data not shown). To
evaluate the transporter-mediated specific uptake, nonspecific uptake
was evaluated by measuring in the presence of inhibitors (Fig.
2, A and B). As
shown in Fig. 2C, the specific uptake of
[14C]Gly-Sar tended to be lower in the light phase than
the dark phase. For example, the [14C]Gly-Sar specific
uptake value was significantly greater at 2400 h (6.1 ± 0.6 nmol/g tissue) than at 1200 h (5.0 ± 0.5 nmol/g tissue) (n = 15 segments from 5 rats; P < 0.05). A similar result was obtained in the [14C]
MG
uptake experiments (Fig. 2D).
|
Diurnal variation of PEPT1 and SGLT1 proteins in the duodenum.
To determine whether the rhythmicity of [14C]Gly-Sar
uptake was linked to expressional changes of PEPT1 protein, we
performed Western blot analysis using intestinal brush-border
membranes. As shown in Fig.
3A, the intestinal PEPT1
protein level was highest at 2000 and lowest at 800. A similar pattern
of expression was observed for SGLT1 protein (Fig.
3B), and this result was consistent with the previous
reports (30, 42). In contrast to both proteins, villin,
which is a cytoskeletal marker protein, did not change in expressional
level throughout the day (Fig. 3C).
|
|
Diurnal variation of PEPT1, PEPT2, and SGLT1 proteins in the
kidney.
The diurnal variation in the expression of PEPT1 and SGLT1 protein in
the kidney was tested further (Fig. 5,
A and C). In contrast to their expressional
rhythmicity in the duodenum, levels of PEPT1 and SGLT1 protein
expression in the kidney did not vary appreciably during the 24-h
period. The protein level of PEPT2, which is another
H+-peptide transporter predominantly expressed in the
kidney, also showed little diurnal variation (Fig. 5B).
|
Diurnal variation of PEPT1 and SGLT1 mRNAs in the duodenum.
To assess whether diurnal variation in PEPT1 expression occurred at the
transcriptional level, Northern blot analysis was carried out. As shown
in Fig. 6A, significantly more
PEPT1 mRNA was present in the small intestine from 1600 to 2400 than at
other times. Similar expressional changes were observed for the SGLT1 mRNA (Fig. 6B). On the other hand, the GAPDH mRNA level
exhibited no significant diurnal variations (Fig. 6C).
|
Diurnal variation of PEPT1, PEPT2, and SGLT1 mRNA in the kidney.
We further investigated the diurnal rhythm of PEPT1, PEPT2, and SGLT1
mRNA expression in rat kidney. As shown in Fig.
7, mRNAs of all the transporters
exhibited no apparent diurnal variation.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Intestinal PEPT1 is physiologically regulated by various factors including dietary conditions (10, 15, 27, 34), hormones (6, 43), growth factors (25), and development (33). Dietary regulation of intestinal PEPT1 has been extensively investigated (10, 15, 27, 34). For example, we previously demonstrated that short-term starvation markedly increased the amount of PEPT1 protein, whereas dietary administration of amino acids reduced the amount (27). Taking these findings into consideration, it is expected that food content and feeding schedule affect the diurnal rhythmicity of intestinal PEPT1. The aim of the present study is to clarify whether rat PEPT1 shows a diurnal rhythmicity under standard environmental conditions. Therefore, we performed each experiment using rats maintained in a 12-h photoperiod with free access to water and standard laboratory chow.
The present study has demonstrated that transport activity and
expression level (both mRNA and protein) of intestinal PEPT1 and SGLT1
showed diurnal rhythm. Transport activity and expression levels of both
transporters appeared to be higher in the dark phase than the light
phase. A similar diurnal rhythm has been observed for various
intestinal digestive and absorptive activities, such as
sucrase-isomaltase (37), lactase (38),
-glutamyltransferase (38), alkaline phospatase
(38), and glucose and L-histidine transport
(12). In addition to the above functional rhythmicity, recent studies have clarified that the expressional rhythms of SGLT1
and facilitative glucose transporters (GLUT2 and GLUT5) are related to
these functional rhythms (8, 30, 42). Because rodents show
a nocturnal feeding behavior, all of these diurnal rhythms, including
the PEPT1 rhythmicity, could seem reasonable for the preparation of
nocturnal dietary load.
In the present study, we found that the diurnal rhythm of the expression of intestinal PEPT1 protein is linked with the periodicity of the transcription of the PEPT1 mRNA. But it remains unclear what factors regulate the transcription of intestinal PEPT1. In the case of SGLT1, Tavakkolizadeh et al. (42) suggested two distinct and separate pathways regulating the expression and function in intestinal epithelial cells. One pathway is the utilization of gut luminal signals (presumably food intake) to induce the diurnal variation. This mechanism may be involved in the regulation of PEPT1 rhythmicity, because the dietary regulation of intestinal PEPT1 was reported (10, 15, 27, 34). The second is a daily anticipatory mechanism preparing the intestine for an expected increase in nutrients before exposure to the luminal contents. This mechanism may also contribute to the diurnal rhythm of intestinal PEPT1, because the PEPT1 mRNA level in the small intestine has begun to increase at 1600 before the onset of feeding. It was reported that the bulk of food ingestion occurs in the first 4-6 h of the dark phase when rodents are fed ad libitum (44). It is, therefore, hypothesized that these two factors have complexly influenced the diurnal variation of the intestinal PEPT1 expression.
Rhoads et al. (30) demonstrated that the periodicity in the activity of hepatocyte nuclear factor 1 (HNF-1) contributed to the circadian rhythm of SGLT1 transcription. Because it was reported that there is a potential site for HNF-1 in the rat PEPT1 promoter region (34), this factor may be involved in the daily anticipatory mechanism of intestinal PEPT1 expression. A neuroendocrine mechanism, such as insulin circadian variation, was also proposed to affect the glucose absorption in rats (5, 14). Likewise, insulin was demonstrated to regulate the PEPT1 function by increasing the population of PEPT1 protein in membranes (43). These findings suggest that insulin circadian variation may affect the PEPT1 expression and function, although this mechanism is not involved in the transcriptional regulation. More recently, Buyse et al. (6) reported that PEPT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by gastric leptin, the ob gene product, on the luminal side of the small intestine. Although the diurnal rhythm of gastric leptin secretion into the lumen has not been investigated, there are various reports on the circadian rhythm of the plasma leptin levels (2, 3, 22). Thus the luminal leptin secreted by the stomach could be involved in the diurnal rhythm of intestinal PEPT1 expression.
In contrast to the intestinal PEPT1 and SGLT1 expression, the mRNA expression of both transporters in the kidney showed little diurnal rhythmicity. Crypt-villus turnover in the intestine has been demonstrated to show a circadian rhythm; i.e., enterocyte differentiation is increased and peaks at 300 in a 12:12-h light-dark cycle beginning at 600 (35). In addition, the length of the villus and the number of mature enterocytes peak before the onset of feeding (36). However, to our knowledge, there are few reports on the circadian rhythms of cell differentiation and number in renal tubular cells. It is, therefore, assumed that some distinct features of cell dynamics between the intestinal and renal epithelial cells contribute to the different diurnal rhythmicities of the intestinal and renal PEPT1 and SGLT1 expressions. Alternatively, transcription factors, such as HNF-1 may have different effects in the small intestine than in the kidney. Clarification of the regulatory mechanisms of PEPT1 and SGLT1 expression in both tissues should be useful for the understanding of the circadian rhythm of PEPT1 and SGLT1 expression in the small intestine.
Several drugs vary in potency and/or toxicity on the basis of the
rhythmicity of biochemical, physiological, and behavioral processes
(19, 21). For example, chronopharmacotherapy with interferon- in mice has been studied, and the dosing time-dependent change in antiviral activity was partly explained by the diurnal variation of pharmacokinetic parameters of interferon-
(18, 28). Because intestinal PEPT1 mediated a wide variety
of peptide-like drugs, such as oral
-lactam anitibiotics and the
antivirus agent valacyclovir (17), the absorption rate and
therapeutic efficacy of these drugs would depend largely on the
activity of PEPT1. Although further study is needed, there is a
possibility that the pharmacokinetic profiles and therapeutic efficacy
of these drugs may be affected by the dosing time schedule.
In conclusion, the present study has demonstrated that the functional activity and expression of intestinal, but not renal, PEPT1 show a diurnal rhythm as well as SGLT1. The diurnal rhythm of intestinal PEPT1 expression occurred in the transcription.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Dr. K. Takata, Department of Anatomy and Cell Biology, Gunma University School of Medicine, for helpful discussion about the immunohistochemistry of PEPT1 in the duodenum.
![]() |
FOOTNOTES |
---|
This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Address for reprint requests and other correspondence: K. Inui, Dept. of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan (E-mail: inui{at}kuhp.kyoto-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00545.2001
Received 28 December 2001; accepted in final form 5 February 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Adibi, SA.
The oligopeptide transporter (Pept-1) in human intestine: biology and function.
Gastroenterology
113:
332-340,
1997[ISI][Medline].
2.
Ahmad, AM,
Guzder R,
Wallace AM,
Thomas J,
Fraser WD,
and
Vora JP.
Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement.
J Clin Endocrinol Metab
86:
3499-3506,
2001
3.
Ankarberg-Lindgren, C,
Dahlgren J,
Carlsson B,
Rosberg S,
Carlsson L,
Wikland KA,
and
Norjavaara E.
Leptin levels show diurnal variation throughout puberty in healthy children, and follow a gender-specific pattern.
Eur J Endocrinol
145:
43-51,
2001[ISI][Medline].
4.
Baril, EF,
and
Potter VR.
Systematic oscillations of amino acid transport in liver from rats adapted to controlled feeding schedules.
J Nutr
95:
228-237,
1968[ISI].
5.
Bellinger, LL,
Mendel VE,
and
Moberg GP.
Circadian insulin, GH, prolactin, corticosterone and glucose rhythms in fed and fasted rats.
Horm Metab Res
7:
132-135,
1975[ISI].
6.
Buyse, M,
Berlioz F,
Guilmeau S,
Tsocas A,
Voisin T,
Péranzi G,
Merlin D,
Laburthe M,
Lewin MJM,
Rozé C,
and
Bado A.
PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine.
J Clin Invest
108:
1483-1494,
2001
7.
Chirgwin, JM,
Przybyla AE,
MacDonald RJ,
and
Rutter WJ.
Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
Biochemistry
18:
5294-5299,
1979[ISI][Medline].
8.
Corpe, CP,
and
Burant CF.
Hexose transporter expression in rat small intestine: effect of diet on diurnal variations.
Am J Physiol Gastrointest Liver Physiol
271:
G211-G216,
1996
9.
Daniel, H,
and
Herget M.
Cellular and molecular mechanisms of renal peptide transport.
Am J Physiol Renal Physiol
273:
F1-F8,
1997
10.
Erickson, RH,
Gum JR, Jr,
Lindstrom MM,
Mckean D,
and
Kim YS.
Regional expression and dietary regulation of rat small intestinal peptide and amino acid transporter mRNAs.
Biochem Biophys Res Commun
216:
249-257,
1995[ISI][Medline].
11.
Feigin, RD,
Dangerfield HG,
and
Beisel WR.
Circadian periodicity of blood amino-acids in normal and adrenalectomized mice.
Nature
221:
94-95,
1969[ISI].
12.
Furuya, S,
and
Yugari Y.
Daily rhythmic change of L-histidine and glucose absorptions in rat small intestine in vivo.
Biochim Biophys Acta
343:
558-564,
1974[ISI][Medline].
13.
Grimble, GK.
The significance of peptides in clinical nutrition.
Annu Rev Nutr
14:
419-447,
1994[ISI][Medline].
14.
Hara, E,
and
Saito M.
Diurnal changes in plasma glucose and insulin responses to oral glucose load in rats.
Am J Physiol Endocrinol Metab
238:
E463-E466,
1980
15.
Ihara, T,
Tsujikawa T,
Fujiyama Y,
and
Bamba T.
Regulation of PEPT1 peptide transporter expression in the rat small intestine under malnourished conditions.
Digestion
61:
59-67,
2000[ISI][Medline].
16.
Inui, K,
Okano T,
Takano M,
Saito H,
and
Hori R.
Carrier-mediated transport of cephalexin via the dipeptide transport system in rat renal brush-border membrane vesicles.
Biochim Biophys Acta
769:
449-454,
1984[ISI][Medline].
17.
Inui, K,
and
Terada T.
Dipeptide transporters
In: Membrane Transporters as Drug Targets, edited by Amidon GL,
and Sadée W.. New York: Kluwer Academic/Plenum, 1999, p. 269-288.
18.
Koyanagi, S,
Ohdo S,
Yukawa E,
and
Higuchi S.
Chronopharmacological study of interferon- in mice.
J Pharmacol Exp Ther
283:
259-264,
1997
19.
Labrecque, G,
and
Bélanger PM.
Biological rhythms in the absorption, distribution, metabolism and excretion of drugs.
Pharmacol Ther
52:
95-107,
1991[ISI][Medline].
20.
Leibach, FH,
and
Ganapathy V.
Peptide transporters in the intestine and the kidney.
Annu Rev Nutr
16:
99-119,
1996[ISI][Medline].
21.
Lemmer, B,
Scheidel B,
and
Behne S.
Chronopharmacokinetics and chronopharmacodynamics of cardiovascular active drugs. Propranolol, organic nitrates, nifedipine.
Ann NY Acad Sci
618:
166-181,
1991[ISI][Medline].
22.
Marie, M,
Findlay PA,
Thomas L,
and
Adam CL.
Daily patterns of plasma leptin in sheep: effects of photoperiod and food intake.
J Endocrinol
170:
277-286,
2001
23.
Motohashi, H,
Masuda S,
Katsura T,
Saito H,
Sakamoto S,
Uemoto S,
Tanaka K,
and
Inui K.
Expression of peptide transporter following intestinal transplantation in the rat.
J Surg Res
99:
294-300,
2001[ISI][Medline].
24.
Nakashima, E,
Tsuji A,
Mizuo H,
and
Yamana T.
Kinetics and mechanism of in vitro uptake of amino -lactam antibiotics by rat small intestine and relation to the intact-peptide transport system.
Biochem Pharmacol
33:
3345-3352,
1984[ISI][Medline].
25.
Nielsen, CU,
Amstrup J,
Steffansen B,
Frokjaer S,
and
Brodin B.
Epidermal growth factor inhibits glycylsarcosine transport and hPepT1 expression in a human intestinal cell line.
Am J Physiol Gastrointest Liver Physiol
281:
G191-G199,
2001
26.
Ogihara, H,
Saito H,
Shin BC,
Terada T,
Takenoshita S,
Nagamachi Y,
Inui K,
and
Takata K.
Immuno-localization of H+/peptide contransporter in rat digestive tract.
Biochem Biophys Res Commun
220:
848-852,
1996[ISI][Medline].
27.
Ogihara, H,
Suzuki T,
Nagamachi Y,
Inui K,
and
Takata K.
Peptide transporter in the rat small intestine: ultrastructural localization and the effect of starvation and administration of amino acids.
Histochem J
31:
169-174,
1999[ISI][Medline].
28.
Ohdo, S,
Wang DS,
Koyanagi S,
Takane H,
Inoue K,
Aramaki H,
Yukawa E,
and
Higuchi S.
Basis for dosing time-dependent changes in the antiviral activity of interferon- in mice.
J Pharmacol Exp Ther
294:
488-493,
2000
29.
Okano, T,
Inui K,
Takano M,
and
Hori R.
H+ gradient-dependent transport of aminocephalosporins in rat intestinal brush-border membrane vesicles: role of dipeptide transport system.
Biochem Pharmacol
35:
1781-1786,
1986[ISI][Medline].
30.
Rhoads, DB,
Rosenbaum DH,
Unsal H,
Isselbacher KJ,
and
Levitsky LL.
Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is transcriptionally regulated.
J Biol Chem
273:
9510-9516,
1998
31.
Saito, H,
Okuda M,
Terada T,
Sasaki S,
and
Inui K.
Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of -lactam antibiotics in the intestine and kidney.
J Pharmacol Exp Ther
275:
1631-1637,
1995[Abstract].
32.
Saito, H,
Terada T,
Okuda M,
Sasaki S,
and
Inui K.
Molecular cloning and tissue distribution of rat peptide transporter PEPT2.
Biochim Biophys Acta
1280:
173-177,
1996[ISI][Medline].
33.
Shen, H,
Smith DE,
and
Brosius FC, III.
Developmental expression of PEPT1 and PEPT2 in rat small intestine, colon and kidney.
Pediatr Res
49:
789-795,
2001
34.
Shiraga, T,
Miyamoto K,
Tanaka H,
Yamamoto H,
Taketani Y,
Morita K,
Tamai I,
Tsuji A,
and
Takeda E.
Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1.
Gastroenterology
116:
354-362,
1999[ISI][Medline].
35.
Sigdestad, CP,
Bauman J,
and
Lesher SW.
Diurnal fluctuations in the number of cells in mitosis and DNA synthesis in the jejunum of the mouse.
Exp Cell Res
58:
159-162,
1969[ISI][Medline].
36.
Stevenson, NR,
Day SE,
and
Sitren HS.
Circadian rhythmicity in the rat intestinal villus length and cell number.
J Chronobiol
6:
1-12,
1979.
37.
Stevenson, NR,
and
Fierstein JS.
Circadian rhythms of intestinal sucrase and glucose transport: cued by time of feeding.
Am J Physiol
230:
731-735,
1976
38.
Stevenson, NR,
Sitren HS,
and
Furuya S.
Circadian rhythmicity in several small intestinal functions is independent of use of the intestine.
Am J Physiol Gastrointest Liver Physiol
238:
G203-G207,
1980
39.
Takahashi, K,
Nakamura N,
Terada T,
Okano T,
Futami T,
Saito H,
and
Inui K.
Interaction of -lactam antibiotics with H+/peptide cotransporters in rat renal brush-border membranes.
J Pharmacol Exp Ther
286:
1037-1042,
1998
40.
Takata, K,
Kasahara T,
Kasahara M,
Ezaki O,
and
Hirano H.
Localization of Na+-dependent active type and erythrocyte/HepG2-type glucose transporters in rat kidney: immunofluorescence and immunogold study.
J Histochem Cytochem
39:
287-298,
1991[Abstract].
41.
Takeuchi, A,
Masuda S,
Saito H,
Doi T,
and
Inui K.
Role of kidney-specific organic anion transporters in the urinary excretion of methotrexate.
Kidney Int
60:
1058-1068,
2001[ISI][Medline].
42.
Tavakkolizadeh, A,
Berger UV,
Shen KR,
Levitsky LL,
Zinner MJ,
Hediger MA,
Ashley SW,
Whang EE,
and
Rhoads DB.
Diurnal rhythmicity in intestinal SGLT-1 function, Vmax, and mRNA expression topography.
Am J Physiol Gastrointest Liver Physiol
280:
G209-G215,
2001
43.
Thamotharan, M,
Bawani SZ,
Zhou XD,
and
Adibi SA.
Hormonal regulation of oligopeptide transporter PEPT1 in a human intestinal cell line.
Am J Physiol Cell Physiol
276:
C821-C826,
1999
44.
Vachon, C,
and
Savoie L.
Circadian variation of food intake and digestive tract contents in the rat.
Physiol Behav
39:
629-632,
1987[ISI][Medline].
45.
Wurtman, RJ,
Shoemaker WJ,
and
Larin F.
Mechanism of the daily rhythm in hepatic tyrosine transaminase activity: role of dietary tryptophan.
Proc Natl Acad Sci USA
59:
800-807,
1968[ISI][Medline].