ORGANIC CATION/CARNITINE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 41

Tissue Distribution and Cellular Membrane Localization CT2 is expressed in the
testis by Sertoli cells and by epithelial cells of the epididymal ducts. 37 CT2 mRNA
is further expressed in fetal liver, bone marrow, leukocytes, and some leukemic cell
lines. 38 CT2 translocates carnitine in either direction across the plasma membrane
and may thus contribute to the transepithelial transport of carnitine in the epididy-
mus. In human mammary gland, Kwok et al. 39 have demonstrated that Flipt2/OCT6,
a splice variant of CT2, can coexist with ATB(0 + ) in a network of multiple SLC
organic cation/nutrient transporters in drug transfer. Among other SLC22 family
transporters, they found hOCTN1 and hOCTN2, and besides hOCT1 and hOCT3
in the mammary gland epithelial cell line, MCF12A. Modeling analysis predicted
multiplicity of uptake mechanisms with the high-affinity systems characterized by a
K m of 5.1 M for carnitine and 1.6 mM for TEA, respectively, apparently similar

to the hOCTN2 parameter reported for carnitine and that of EMT/hOCT3 for TEA.
Verapamil, cimetidine, carbamazepine. quinidine, and desipramine inhibited carni-
tine uptake but required supratherapeutic concentrations, suggesting the robustness
of carnitine uptake systems against xenobiotic challenge.

μ

3.2.5. Comparison with Other Carnitine Transporters
ATB( 0 + ) Transporter Nakanishi et al. 40 identified a second energy-coupled carnitine
transporter, called amino acid transporter system B(0 + ) [ATB(0 + )]. It is primarily
an amino acid transporter 40 and plays an important role in the intestine. ATB(0 + )is
also expressed in the lung, mammary gland, and eye. It is a Na + - and Cl − -coupled
transport system for neutral and cationic amino acids. Many of the amino acids and
amino acid derivatives that serve as substrates for ATB(0 + ) are therapeutic agents (e.g.,
D-serine, carnitine, and nitric oxide synthase inhibitors). Recent studies have shown
that the potential of ATB(0 + ) as a drug delivery system may be greater than previously
envisaged. 41 Taylor 42 speculated that the mature intestine may have an active transport
and a passive carnitine diffusion mechanism, representing contributions from OCTN2
and ATB(0 + ), respectively. We investigated the influence of Cl − on intestinal carnitine
uptake by replacing it from the uptake buffer with NaH 2 PO 4 , and noted no effect. 3 We
also tested known amino acid substrates of ATB(0 + ) and noted that neither leucine
nor tryptophan inhibited carnitine transport in Caco-2 cells. In the mammary gland
epithelia, ATB(0 + ) can exist in a network of various transporters, with hOCTN1,
hOCTN2, and Flipt2/OCT6 (a splice variant of CT2). 39 Berezowski et al. 43 have
shown that OCTN2 and ATB(0 + ) could be involved in carnitine transport in both the
apical and basolateral membranes of brain capillary epithelial cells.

3.3. CLINICAL IMPLICATIONS

The physiological significance of organic cation/carnitine transporters in humans is
highlighted by the identification of the hereditary disorder caused by mutations in
the gene encoding for OCTN2 protein, an autosomal recessive disease known as
primary systemic carnitine deficiency (SCD). 1 More commonly, secondary carnitine