EDITORIAL FOCUS
Intestinal absorption of water-soluble
vitamins Focus on "Molecular mechanism of the
intestinal biotin transport process"
Krishnamurthy
Ramaswamy
Section of Digestive and Liver Diseases, Department of Medicine,
University of Illinois at Chicago and the Westside Veterans Affairs
Medical Center, Chicago, Illinois 60612
 |
ARTICLE |
THE WATER-SOLUBLE VITAMINS represent a structurally and
functionally distinct set of organic compounds that are essential for
human health. It has long been recognized that they play a vital role
in intermediary metabolism, energy production, and cell differentiation
and proliferation (1, 4). Mammals, including humans, have lost their
ability to synthesize these compounds and, therefore, must obtain them
from diet and other exogenous sources (1, 4). Biotin deficiency in
humans is associated with a range of clinical abnormalities, including
neurological disorders, growth retardation, and skin abnormalities (1,
4). The cellular assimilation and function of vitamins are to a large extent dependent on their absorption via the gastrointestinal tract,
making the studies of their intestinal absorption mechanisms and
regulation extremely important. Although originally assumed to be
absorbed by passive diffusion processes, intestinal absorption of these
micronutrients has been shown to occur by specialized transport
mechanisms (6-8). The current article in focus by Chatterjee et
al. (Ref. 3, see page C605 in this issue) represents a
significant contribution from a group of researchers who for many years
have been carrying out studies of mechanisms and regulation of
intestinal transport of a number of water-soluble vitamins at the
tissue, cellular, membrane, and molecular levels. The study in focus
describes the molecular characterization of the intestinal absorption
process of one of the water-soluble vitamins, namely, biotin.
Biotin, also known as vitamin H and coenzyme R, acts as an essential
coenzyme for four carboxylases that catalyze the incorporation of
cellular bicarbonate into metabolically important organic compounds (1,
4). For example, the enzyme acetyl carboxylase catalyzes the formation
of malonyl-CoA, which serves an important function as a substrate for
fatty acid synthesis. The other biotin-requiring carboxylases are
involved in gluconeogenesis and fatty acid and branched-chain amino
acid metabolism. The mammalian intestine is exposed to biotin derived
from the diet and from synthesis by normal colonic microflora. Similar
to studies of intestinal transport of a number of nutrients, the
chronology for biotin has evolved from an initial belief that the
transport process is nonspecific and occurs by a simple diffusion
process, to identification of a carrier-mediated system and its
physiological and biochemical characterization using tissue slices and
membrane vesicles, and finally to the current cloning of the transport
protein involved (8). In the last decade, independent studies by Brown
and Rosenberg (2) and Said and Redha (14), using intact small
intestinal tissue preparations, have shown the involvement of a
Na+-dependent, carrier-mediated
mechanism for biotin transport in the rat small intestine. Subsequent
studies from the laboratory of Said, using purified intestinal apical
and basolateral membrane preparations, have demonstrated that the
Na+-dependent, carrier-mediated
process is localized in the apical domain of enterocytes (9, 13, 17).
It was also shown that an outwardly directed
Na+ gradient energized the
transport of biotin across the apical membrane. The transport process
was found to be electroneutral with a
biotin
/Na+
stoichiometric coupling ratio of 1:1. Recently, exciting and unexpected
results regarding the function of the human colon in biotin transport
revealed the presence of a similar transport process in human colonic
apical membranes (12). These findings are very significant, because the
transport process can be expected to fully utilize the biotin
synthesized in the colonic lumen by bacteria. Regarding the efflux
mechanism for biotin that is important for tissues other than the
intestine, transport of biotin across the basolateral membrane domain
was shown to occur by a
Na+-independent, carrier-mediated
process (16).
Regional differences in transport characteristics for biotin have been
shown, with the duodenum showing higher transport rates than the ileum
(11, 14). The higher transport rates were shown to be related to an
increase in maximal velocity rather than the Michaelis-Menten constant,
indicating a higher number of carriers or increased turnover in the
proximal part of the small intestine. Various studies of regulation of
biotin transport have also shown ontogenic effects as well as
regulation by extracellular substrate levels and protein
kinase-mediated pathways (8, 10, 12, 15).
A very interesting recent development in this area was the
demonstration that the biotin transport system could be shared by an
unrelated water-soluble vitamin, pantothenic acid (8, 12). However, the
physiological and nutritional implications of such a vitamin-vitamin
interaction at the transporter level are not currently understood.
Future studies should focus on this important question, in view of the
presence of >200-fold higher levels of pantothenic acid compared with
biotin in the diet and the importance of both vitamins for vital
metabolic functions.
The current article in focus describes the molecular characterization
of an intestinal biotin transporter (3). These investigators have
isolated three variants of the recently described placental transporter. It is noteworthy that the isolation of the placental transporter cDNA was purely serendipitous, in that those investigators initiated their search for a cationic transporter that ended up in the
discovery of an anionic transporter (5). The three variants described
in the investigations of Chatterjee et al. (3) are significant, in that
they have the same open reading frame as the placental variant but
differ in the 5' untranslated end. Furthermore, the placental
variant was not found in the small intestine. These results clearly
point to the potential for future studies to investigate the
transcriptional regulation of this transporter, to understand the
tissue-specific expression and other regulatory mechanisms in its
expression. The authors have transfected the cDNA into COS-7 cells and
have confirmed that the transporter characteristics of the cloned
transporter are similar to what they have observed in native intestinal
membranes regarding substrate specificity, kinetics, and inhibitor
profiles. It is clear that the molecular characterization of the
intestinal biotin transport process described in this report will
greatly assist in future investigations aimed at an understanding of
the molecular regulation of the transport process of this essential
micronutrient, not only in the intestine but also in other tissues that
are involved in regulating biotin homeostasis.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: K. Ramaswamy, Section of Digestive and Liver Diseases, Dept. of
Medicine, Univ. of Illinois at Chicago, 840 South Wood St., Rm 718E,
Chicago, IL 60612-7323 (E-mail:
kramaswa{at}uic.edu).
 |
REFERENCES |
1.
Bonjour, J.
Biotin.
In: Handbook of Vitamins: Nutritional Biochemical and Clinical Aspects, edited by L. Machlin. New York: Dekker, 1984, p. 403-435.
2.
Brown, B.,
and
J. Rosenberg.
Biotin absorption by distal rat intestine.
J. Nutr.
117:
2121-2126,
1987[Medline].
3.
Chatterjee, N. S.,
C. K. Kumar,
A. Ortiz,
S. A. Rubin,
and
H. M. Said.
Molecular mechanism of the intestinal biotin transport process.
Am. J. Physiol.
277 (Cell Physiol. 46):
C605-C613,
1999[Abstract/Free Full Text].
4.
Dakshinamurti, K.,
and
J. Chauhan.
Regulation of biotin enzymes.
Annu. Rev. Nutr.
8:
211-233,
1988[Medline].
5.
Prasad, P. D.,
H. Wang,
R. Kekuda,
T. Fujita,
Y. J. Fei,
L. D. Devoe,
F. H. Leibach,
and
V. Ganapathy.
Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate.
J. Biol. Chem.
273:
7501-7506,
1998[Abstract/Free Full Text].
6.
Rose, R. C.
Intestinal absorption of water-soluble vitamins.
Proc. Soc. Exp. Biol. Med.
212:
191-198,
1996[Abstract].
7.
Rose, R. C.
Water-soluble vitamin absorption in intestine.
Annu. Rev. Physiol.
42:
157-171,
1980[Medline].
8.
Said, H. M.
Cellular uptake of biotin: mechanisms and regulation.
J. Nutr.
129, Suppl 25:
490S-493S,
1999[Medline].
9.
Said, H. M.,
and
I. Derweesh.
Carrier-mediated mechanism for biotin transport in rabbit intestine: studies with brush-border membrane vesicles.
Am. J. Physiol.
261 (Regulatory Integrative Comp. Physiol. 30):
R94-R97,
1991[Abstract/Free Full Text].
10.
Said, H. M.,
D. Mock,
and
J. Collins.
Regulation of intestinal biotin transport in the rat: effect of biotin deficiency and supplementation.
Am. J. Physiol.
256 (Gastrointest Liver Physiol. 19):
G306-G311,
1989[Abstract/Free Full Text].
11.
Said, H. M.,
W. Nylander,
and
R. Redha.
Biotin transport in human intestine: site of maximum transport and effect of pH.
Gastroenterology
95:
1312-1317,
1988[Medline].
12.
Said, H. M.,
A. Ortiz,
E. McCloud,
D. Dyer,
M. P. Moyer,
and
S. Rubin.
Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid.
Am. J. Physiol.
275 (Cell Physiol. 44):
C1365-C1371,
1999.
13.
Said, H. M.,
and
R. Redha.
Biotin transport in rat intestinal brush-border membrane vesicles.
Biochim. Biophys. Acta
945:
195-201,
1988[Medline].
14.
Said, H. M.,
and
R. Redha.
A carrier-mediated transport system for biotin in rat intestine in vitro.
Am. J. Physiol.
252 (Gastrointest Liver Physiol. 15):
G52-G55,
1987[Abstract/Free Full Text].
15.
Said, H. M.,
and
R. Redah.
Ontogenesis of the intestinal transport of biotin in the rat.
Gastroenterology
94:
68-72,
1988[Medline].
16.
Said, H. M.,
R. Redha,
and
W. Nylander.
Biotin transport in basolateral membrane vesicles of human intestine.
Gastroenterology
94:
1157-1163,
1988[Medline].
17.
Said, H. M.,
R. Redha,
and
W. Nylander.
A carrier-mediated Na+ gradient-dependent transport for biotin in human intestinal brush-border membrane vesicles.
Am. J. Physiol.
253 (Gastrointest Liver Physiol. 16):
G631-G636,
1987[Abstract/Free Full Text].
Am J Physiol Cell Physiol 277(4):C603-C604