Biomedical Engineering Reference
In-Depth Information
diabetes, MCT1 expression is reported to be reduced in the heart, in adipose tissue,
and together with MCT4, in skeletal muscle,
838
,
839
although previous studies reported
contrasting results.
985
In another study, MCT1 content in skeletal muscle of patients
with type 2 diabetes was lower than in the muscle of healthy men. In addition, training
increased MCT1 content in both groups, whereas in healthy people, but not in patients
with type 2 diabetes, MCT4 increased in response to training.
840
In brain tissue, MCT expression levels were found to vary in endothelial and
parenchymal cells during peri- and postnatal development in rats. For instance, it was
observed that endothelial mature astrocytes and parenchymal cells in rat brain have
increased levels of MCT1 postnatally, an increase after weaning, and quite high levels
at adulthood. These modifications in MCT expression seem to reflect formation of
the blood-brain barrier and the switch in the postnatal period from a prevalent use of
monocarboxylates to glucose utilization by the adult brain.
841
Furthermore, in adult
rat a ketogenic diet as well as ischemic conditions were reported to induce brain
MCT1 expression.
842
,
843
Moreover, in cultured cortical neurons, MCT2 expression
was enhanced by noradrenalin, suggesting that MCT expression may be regulated
by synaptic activity.
844
,
845
In addition, treatment of rat brain endothelial cells by
cobalt chloride increased MCT1 expression.
817
In retinal explants, MCT1 was in-
duced by hypoxia and vascular endothelial growth factor,
817
,
846
whereas in cultured
macrophages, lipopolysaccharides and tumor necrosis factor-
determine increased
expression of MCT1.
847
In human colonic epithelial cells, treatment with butyrate has been reported to up-
regulate MCT1 expression, and exposure to leptin, a hormone involved in regulation
of cellular metabolism, was able to further increase butyrate uptake.
848
,
849
In rat,
treatment with testosterone has recently been associated with an increase in MCT1
and MCT4 proteins in skeletal muscles but not in the heart.
850
Finally, as MCT1 and
MCT4 activity has been linked to the expression of some membrane glycoproteins
(e.g., GP-70 in humans, CD147, OX-47, basigin, etc., in other species), overexpression
of these glycoproteins by several factors can modulate the expression and activity of
MCT transporters.
851
,
852
Pharmacological and Toxicological Function
In view of their cellular location and
tissue distribution, it has been proposed that MCTs, in particular MCT1, can be
involved in intestinal absorption, blood-brain transport, and liver delivery of some
weak organic acid drugs. MCTs may be involved in the intestinal absorption of some
-lactam antibiotics and nonsteroidal anti-inflammatory drugs, as they are reported to
be good MCT substrates in vitro.
817
In addition, as monocarboxylate activity is proton
dependent, the transport of substrate drugs by MCTs across the epithelial layer of the
small intestine may be facilitated by the presence, at the luminal side of the brush
border membrane, of a low pH. This creates a proton gradient that could facilitate the
monocarboxylate transport.
853
MCT1 expression at the blood-brain barrier may play
a crucial role in the efflux of certain drugs from the brain. Indeed, the low distribution
of probenecid and 6-mercaptopurine in the brain has been proposed to depend in part
on their MCT-mediated efflux.
854
,
855
The tissue-specific expression of MCTs may also explain the development of
certain side effects that follow the intake of a range of MCT substrate drugs. For
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