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Research
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SLC10 transporters:
New insights into an old carrier family
The
SLC10 carrier family
Clock-enforced Bayesian cDNA tree with lineages-through-time plot
of mammalian and non-mammalian members of the SLC10 family.
Until
2004 the solute carrier family 10 (SLC10) was known as the „sodium
bile acid cotransporter family“ and comprised only two bile
acid carriers; namely, the Na+/taurocholate cotransporting polypeptide
(NTCP, SLC10A1) and the apical sodium-dependent bile acid transporter
(ASBT, SLC10A2). To date, we identified and cloned several new members
(SLC10A4 to SLC10A7) that highly differ in expression pattern and
transport characteristics. E.g., the sodium-dependent organic anion
transporter (SOAT) is highly expressed in organs of reproduction
such as testis and placenta and transports sulfoconjugated steroid
hormones rather than bile acids. By analyzing the phylogenetic relationship
and evolutionary origin of the SLC10 family, we found two major
clades of genes. Within major clade I SOAT is the sister group of
ASBT and SLC10A4 is the sister group of NTCP.
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SLC10A1 (NTCP) and SLC10A2 (ASBT)
are the founding members of the SLC10 family and were cloned by
expression cloning in the early 90’s. Both carriers are essentially
involved in the maintenance of the enterohepatic circulation of
bile acids by mediating the first step of active bile acid transport
through the membrane barriers in the liver (NTCP) and intestine
(ASBT).
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SLC10A3
was identified in 1988, before NTCP and ABST were cloned and shows
broad tissue expression pattern. Although known for 20 years, still
no specific function has been found for SLC10A3.
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more
SLC10A4
is an 437 amino acid membrane protein with seven transmembrane domains
and unknown function. Despite its close phylogenetic relationship
to NTCP, SLC10A4 does not tranport bile acids. SLC10A4 is highly
expressed in the brain and exhibits specific localization in neuronal
cell bodies and synapses of cholinergic neurons in the central and
peripheral nervous system.
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SLC10A5
is highly expressed in liver and kindey and here was localized to
hepatocytes and proximal tubules, respectively. SLC10A5 does also
not transport bile acids such as taurocholate and cholate, but we
strongly suppose that SLC10A5 is still a carrier protein but for
other kinds of bile acids or other organic solutes.
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more
SLC10A6
(SOAT)
was cloned in 2004 and is the third member of the SLC10 family that
has been functionally characterized. SOAT does not transport bile
acids such as taurocholic acid, cholic acid, and chenodeoxycholic
acid, but showed sodium-dependent transport activity for sulfoconjugated
steroid hormones such as estrone-3-sulfate, dehydroepiandrosterone
sulfate, and pregnenolone sulfate as well as for sulfoconjugated
bile acids such as sulfotaurolithocholic acid.
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more
SLC10A7
is an 340 amino acid membrane protein with close homolgy to bacterial
proteins. Several characteristics separate SLC10A7 from the other
SLC10 carriers: (I) The SLC10A7 gene comprise 12 coding exons, (II)
the SLC10A7 protein exhibits an 10 transmembrane domain topolgy,
and (III) bile acids as well as sulfoconjugated steroid hormones
are not transported by this carrier.
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more
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Pharmacogenetics
and pharmacogenomics:
Dogs on risk – MDR1 mutation and drug susceptability
The
role of MDR1 in drug disposition
MDR1 (shown as red item) functions as an ATP-driven efflux transporter,
which pumps its substrates out of the cell. The intact MDR1 protein
limits the drug entry into the organism after oral administration,
promotes drug elimination into bile and urine and limits drug penetration
into sensitive tissues (e.g. into the brain, testis and fetal circulation).
In dogs with homozygous MDR1-/- mutation, enteral drug absorption
is enhanced, biliary and urinary drug elimination is reduced, and
the penetration of blood-tissue barriers is increased at the blood-brain
barrier, blood-testis barrier, and blood-placenta barrier. As a
consequence, neurotoxic, nephrotoxic, hepatotoxic drug effects have
to be considered.
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MDR1
mutation in dogs
P-Glycoprotein is an ATP-driven efflux transporter (ABC transporter),
encoded by the multidrug-resistance gene MDR1/ABCB1. It transports
a wide range of structurally unrelated lipophilic and amphipathic
drugs, toxins, and xenobiotics including many commonly used veterinary
drugs. Three decades of research about the physiological significance
of P-glycoprotein have established that the MDR1 efflux machinery
protects the organism from exposure to drugs and environmental xenobiotics
by decreasing their absorption in the intestinal tract and promoting
their excretion into bile and urine. Additionally, MDR1 P-glycoprotein
in the blood-brain barrier highly restricts the entry of drugs and
xenobiotics into the central nervous system. The first reports on
ivermectin neurotoxicity in dogs appeared in a subpopulation of
Collies. Years later, an exonic 4-bp deletion in the MDR1 gene of
these “ivermectin-sensitive Collies” was identified.
Ivermectin toxicosis in affected dogs includes depression, ataxia,
somnolence, salivation, tremor, coma, and death at therapeutic doses
of 0.2 mg/kg b.w. and above. Systematic analyses of breed distribution
of this nt230(del4) MDR1 mutation revealed that besides the Collie,
other genetically related dog breeds are also affected by this mutation,
including herding breeds of the collie lineage (Shetland Sheepdog,
Australian Shepherd, Old English Sheepdog, English Shepherd, Border
Collie, White Swiss Shepherd) and two breeds of the sighthound class
(Longhaired Whippet and Silken Windhound). It was suggested, that
this mutation occurred in an ancestral dog population that lived
in Great Britain in the 1800s, before the emergence of formal breed-lines.
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DMPK:
Drug metabolism and disposition in transporter-deficient knockout
mice
Hepatobiliary drug excretion
Schematic principle of vectorial drug evasion in liver and kidney.
Phase 0 = drug uptake out of blood, Phase 1 and 2 = biotransformation
exemplified by hydroxylation and glucuronidation, Phase 3 = transport
of xenobiotics/metabolites towards excretion, Phase 4 = efflux
into excreted fluids. ¤ = xenobiotic.
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Hepatobiliary excretion and brain penetration
of drugs and toxins
Pharmacokinetics comprises drug liberation, drug absorption, drug
distribution, drug metabolism and drug excretion. The issue of xenobiotic
elimination, also termed evasion, is defined in pharmacokinetics
by two processes, drug metabolism and drug excretion. It has long
been established that transporters exist for endogenous compounds
such as glucose, amino acids, nucleosides, water soluble hormones
and neurotransmitters. However, the perspective that xenobiotics
are also substrates of membrane carriers has emerged only in the
last two decades.
Functional properties of the Phase 4 ATP-driven drug efflux transporters
MDR1, MRP2, and BCRP has intensely been studied by in vitro systems.
The role of these carriere for pharmacokinetics and drug disposition
in vivo is less understood. By use of mdr1a,b-/- and bcrp1-/- knockout
mice as well as mrp2-deficient TR- rats we analyze plasmakinetics,
organ distribution, brain penetration, and in situ biliary excretion
of drugs and toxines in comparison to wildtype mice and Wistar rats,
respectively. In vivo it becomes clear that MDR1 plays a pivotal
role in limiting drug absorption from the gut and blocking drug
entry into the central nervous system. In contrast, MRP2 is the
dominant efflux carrier for hepatobiliary excretion of drug and
toxin conjugates in the liver.
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Christoph Zimmermann
17.09.2009 10:40 
