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

OCTN1 (SLC22A4). OCTN1, cloned originally from human fetal
liver, is expressed in the adult kidney, trachea, and bone marrow
(Tamai et al., 1997). The functional characteristics of OCTN1 suggest
that it operates as an organic cation–proton exchanger. OCTN1-
mediated influx of model organic cations is enhanced at alkaline pH,
whereas efflux is increased by an inwardly directed proton gradient.
OCTN1 contains a nucleotide-binding sequence motif, and transport
of its substrates appears to be stimulated by cellular ATP. OCTN1
also can function as an organic cation–organic cation exchanger.
Although the subcellular localization of OCTN1 has not been
demonstrated clearly, available data collectively suggest that OCTN1
functions as a bidirectional pH- and ATP-dependent transporter at
the apical membrane in renal tubular epithelial cells. OCTN1 appears
to transport the anti-epileptic agent, gabapentin, in the kidney (Urban
et al., 2007).
OCTN2 (SLC22A5). OCTN2 was first cloned from human kidney and
determined to be the transporter responsible for systemic carnitine
deficiency (Tamai et al., 1998). Rat OCTN2 mRNA is expressed predominantly
in the cortex, with very little expression in the medulla,
and is localized to the apical membrane of the proximal tubule.
OCTN2 is a bifunctional transporter, i.e., it transports
L-carnitine with high affinity in an Na + -dependent manner, whereas,
Na + does not influence OCTN2-mediated transport of organic
cations such as TEA. Thus, OCTN2 is thought to function as both an
Na + -dependent carnitine transporter and an Na + -independent organic
cation transporter. Similar to OCTN1, OCTN2 transport of organic
cations is sensitive to pH, suggesting that OCTN2 may function as
an organic cation exchanger. The transport of L-carnitine by OCTN2
is a Na + -dependent electrogenic process, and mutations in OCTN2
appear to be the cause of primary systemic carnitine deficiency
(Nezu et al., 1999).
MATE1 and MATE2-K (SLC47A1 and SLC47A2). Database searches
for human orthologs of bacterial multidrug resistance transporters
have identified two genes in the human genome that code for
membrane transporters (Otsuka et al., 2005). Multidrug and toxin
extrusion family members MATE1 (SLC47A1) and MATE2-K
(SLC47A2) interact with structurally diverse hydrophilic organic
cations including the anti-diabetic drug metformin, the H 2
antagonist
cimetidine, and the anticancer drug, topotecan (Tanihara et al.,
2007). In addition to cationic compounds, the transporters also recognize
some anions, including the antiviral agents acyclovir and ganciclovir.
The zwitterions cephalexin and cephradine are specific substrates
of MATE1, but not MATE2-K. The herbicide paraquat, a
bisquaternary ammonium compound, which is nephrotoxic in
humans, is a potent substrate of MATE1 (Chen et al., 2007). Both
MATE1 and MATE2-K have been localized to the apical membrane
of the proximal tubule (Tanihara et al., 2007). MATE1, but not
MATE2-K, is also expressed on the canalicular membrane of the
hepatocyte. These transporters appear to be the long-searched-for
organic cation proton antiporters on the apical membrane of the
proximal tubule, i.e., an oppositely directed proton gradient can drive
the movement of organic cations via MATE1 or MATE2-K. The
antibiotics, levofloxacin and ciprofloxacin, though potent inhibitors,
are not translocated by either MATE1 or MATE2-K.
Polymorphisms of OCTs. Polymorphisms of OCTs have been identified
in large post–human genome SNP discovery projects (Kerb
et al., 2002; Leabman et al., 2003; Shu et al., 2003). OCT1 exhibits
the greatest number of amino acid polymorphisms, followed by
OCT2 and then OCT3. Furthermore, allele frequencies of OCT1
amino acid variants in human populations generally are greater than
those of OCT2 and OCT3 amino acid variants. Functional studies
of OCT1 and OCT2 polymorphisms have been performed. OCT1
exhibits five variants with reduced function. These variants may have
important implications clinically in terms of hepatic drug disposition
and targeting of OCT1 substrates. In particular, individuals with
OCT1 variants may have reduced liver uptake of OCT1 substrates
and therefore reduced metabolism. Recent studies suggest that
genetic variants of OCT1 and OCT2 are associated with alterations
in the renal elimination and response to the anti-diabetic drug, metformin
(Shu et al., 2007; Song et al., 2008; Wang et al., 2008).
Organic Anion Transport. Myriad structurally diverse
organic anions are secreted in the proximal tubule
(Burckhardt and Burckhardt, 2003; El-Sheikh et al,
2008; Srimaroeng et al., 2008; Wright and Dantzler,
2004). As with organic cation transport, the primary
function of organic anion secretion appears to be the
removal from the body of xenobiotics, including many
weakly acidic drugs [e.g., pravastatin, captopril,
p-aminohippurate (PAH), and penicillins] and toxins
(e.g., ochratoxin). Organic anion transporters move
both hydrophobic and hydrophilic anions but also may
interact with cations and neutral compounds.
A current model for the transepithelial flux of organic anions
in the proximal tubule is shown in Figure 5–13. Two primary transporters
on the basolateral membrane mediate the flux of organic
anions from interstitial fluid to tubule cell: OAT1 (SLC22A6) and
OAT3 (SLC22A8). Energetically, hydrophilic organic anions are
Basolateral
ATP
Luminal
OA –
OA –
OAT4
OAT1
α-KG
α-KG
Urate
OA –
OA – URAT1
OAT3
α-KG
OA –
MRP2
OA – OAT2
ATP
Blood
MRP4
-70mVOA – Urine
Figure 5–13. Model of organic anion secretory transporters in the
proximal tubule. OA, organic anion; α-KG, α-ketoglutarate.
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CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE