DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION I
GENERAL PRINCIPLES
OC +
Basolateral
OC + OC +
Blood
OCT2
OCT3
OCTN1
MDR1
Luminal
H + or OC +
OC +
MATE1
Na + + carnitine
or OC +
OC +
MATE2-K
H +
OC +
ATP
Urine
Figure 5–12. Model of organic cation secretory transporters in
the proximal tubule. OC + , organic cation.
OCT2 (SLC22A2) and OCT3 (SLC22A3). Organic
cations are transported across this membrane down an
electrochemical gradient. Previous studies in isolated
basolateral membrane vesicles demonstrate the presence
of a potential-sensitive mechanism for organic
cations. The cloned transporters OCT2 and OCT3 are
potential sensitive and mechanistically coincide with
previous studies of isolated basolateral membrane
vesicles.
Transport of organic cations from cell to tubular lumen across
the apical membrane occurs via an electroneutral proton–organic
cation exchange mechanism in a variety of species, including human,
dog, rabbit, and cat. The recent discovery of a new transporter family,
SLC47A, multidrug and toxin extrusion family (MATEs), has
provided the molecular identities of the previously characterized
electroneutral proton–organic cation antiport mechanism (Otsuka et
al., 2005; Tanihara et al., 2007). Transporters in the MATE family,
assigned to the apical membrane of the proximal tubule, appear to
play a key role in moving hydrophilic organic cations from tubule
cell to lumen. In addition, novel organic cation transporters
(OCTNs), located on the apical membrane, appear to contribute to
organic cation flux across the proximal tubule. In humans, these
include OCTN1 (SLC22A4) and OCTN2 (SLC22A5). These bifunctional
transporters are involved not only in organic cation secretion
but also in carnitine reabsorption. In the reuptake mode, the transporters
function as Na + co-transporters, relying on the inwardly
driven Na + gradient created by Na + ,K + -ATPase to move carnitine
from tubular lumen to cell. In the secretory mode, the transporters
appear to function as proton–organic cation exchangers. That is, protons
move from tubular lumen to cell interior in exchange for organic
cations, which move from cytosol to tubular lumen. The inwardly
directed proton gradient (from tubular lumen to cytosol) is
maintained by transporters in the SLC9 family, which are Na + /H +
exchangers (NHEs, antiporters). Of the two steps involved in secretory
transport, transport across the luminal membrane appears to be
rate-limiting.
OCT2 (SLC22A2). OCT2 (SLC22A2) was first cloned from a rat kidney
cDNA library in 1996 (Okuda et al., 1996). Human, rabbit,
mouse, and pig orthologs all have been cloned. Mammalian
orthologs range in length from 553 through 555 amino acids.
OCT2 is predicted to have 12 transmembrane domains, including
one N-linked glycosylation site. OCT2 is located adjacent to OCT1
on chromosome 6 (6q26). A single splice variant of human OCT2,
termed OCT2-A, has been identified in human kidney.
OCT2-A, which is a truncated form of OCT2, appears to have a
lower K m
(or greater affinity) for substrates than OCT2, although a
lower affinity has been observed for some inhibitors (Urakami et al.,
2002). Human, mouse, and rat orthologs of OCT2 are expressed in
abundance in human kidney and to some extent in neuronal tissue
such as choroid plexus. In the kidney, OCT2 is localized to the proximal
tubule and to distal tubules and collecting ducts. In the proximal
tubule, OCT2 is restricted to the basolateral membrane. OCT2
mammalian species orthologs are > 80% identical, whereas the
OCT2 paralog found primarily in the liver, OCT1, is ~70% identical
to OCT2. OCT2-mediated transport of model organic cations MPP +
and TEA is electrogenic, and both OCT2 and OCT1 can support
organic cation–organic cation exchange (Koepsell et al., 2007).
OCT2 generally accepts a wide array of monovalent organic cations
with molecular weights < 400 daltons (Ciarimboli, 2008; Koepsell
et al., 2007). The apparent affinities of the human paralogs, OCT1
and OCT2, for some organic cation substrates and inhibitors are different
in side-by-side comparison studies. Isoform-specific
inhibitors of the OCTs are needed to determine the relative importance
of OCT2 and OCT1 in the renal clearance of compounds in
rodents, in which both isoforms are present in kidney. OCT2 is also
present in neuronal tissues; however, monoamine neurotransmitters
have low affinities for OCT2. OCT2 may play a housekeeping role
in neurons, taking up only excess concentrations of neurotransmitters.
OCT2 also may be involved in recycling of neurotransmitters
by taking up breakdown products, which in turn enter monoamine
synthetic pathways.
OCT3 (SLC22A3). OCT3 (SLC22A3) was cloned initially from rat
placenta (Kekuda et al., 1998). Human and mouse orthologs have also
been cloned. OCT3 consists of 551 amino acids and is predicted to
have 12 transmembrane domains, including three N-linked glycosylation
sites. hOCT3 is located in tandem with OCT1 and OCT2 on chromosome
6. Tissue distribution studies suggest that human OCT3 is
expressed in liver, kidney, intestine, and placenta, although it appears
to be expressed in considerably less abundance than OCT2 in the kidney.
Like OCT1 and OCT2, OCT3 appears to support electrogenic potential-sensitive
organic cation transport. Although the specificity of
OCT3 is similar to that of OCT1 and OCT2, it appears to have quantitative
differences in its affinities for many organic cations. Some
studies have suggested that OCT3 is the extraneuronal monoamine
transporter based on its substrate specificity and potency of interaction
with monoamine neurotransmitters. Because of its relatively low abundance
in the kidney (in the basolateral membrane of the proximal
tubule (Koepsell et al., 2007)), OCT3 may play only a limited role in
renal drug elimination.