ORGANIC CATION/CARNITINE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 45

Immunohistochemical studies of renal brush border membrane vesicles by Kato
et al. 66 have revealed that PDZK1 protein and OCTN2 are colocalized in renal brush
border membranes. Double transfection of OCTN2 with PDZK1 stimulated the uptake
by OCTN2 of its endogenous substrate carnitine, and this increase could be accounted
for by the six-fold increase in transport capacity. Such an increase was not observed
for OCTN2 when the last four amino acids were deleted, indicating an interaction
of PDZK1 with the C-terminus of OCTN2. Garcia-Miranda 67 presented evidence to
support the hypothesis that there is a decline in Na + -dependent L-carnitine in the
jejunum and ileum of rats after maturation. Neither delayed weaning nor L-carnitine
supplementation prevented the down-regulation of Na + /L-carnitine transport activity.
These results demonstrate that intestinal Na + -dependent L-carnitine uptake activity
is under genetic regulation at the transcriptional level.

3.5. CONCLUSIONS

This review provides a summary of current knowledge about the physiology and
clinical significance of the OCTN subfamily of organic cation transporters with car-
nitine/cation cotransport function. All three carnitine transporters (OCTN1, 2, and
3), with different characteristics as to affinity, specificity, and tissue distribution, for
example, have wide-ranging clinical importance. There is also evidence to support the
presence of additional carnitine transporters, whose identification, localization, and
functional characterization must be explored further for a complete understanding of
cation/carnitine interactions.
The most physiologically important member of the OCTN group may be con-
sidered to be OCTN2, due to its high affinity for carnitine and expression in many
tissues. A multitude of mutations and single-nucleotide polymorphisms of OCTN2
cause systemic carnitine deficiency syndrome. Recent genetic studies have impli-
cated the IBD5 locus at 5q31, which codes for OCTN1 and OCTN2, in the etiology
of inflammatory bowel disease and rheumatoid arthritis. This region may give rise to
variants that modify transcription and transporter functions of OCTN1 and OCTN2 to
increase susceptibility to CD and UC. Other researchers have speculated that OCTN3
may also be involved in the etiology of IBD. 53 Recent studies also highlight the
pharmacological importance of OCTN transporters, since they transport many drugs,
such as TEA, valproate, verapamil, pyrilamine, and -lactam antibiotics. Short-chain

carnitine esters are also potential drugs transported by OCTN transporters, which
can be designed to correct the anomalies of carnitine transport and resultant mi-
tochondrial energy dysfunction, which are at the root of many clinical syndromes.
The hormonal regulation of OCTN transporters is another developing area of re-
search which may provide guidelines to an understanding of the carnitine/cation
cotransport and how to stimulate their influx into a specific organ and to inhibit their
efflux.

Acknowledgments

This work was supported by a research grant from the Dairy Farmers of Canada.