ORGANIC CATION/CARNITINE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 44

variants modify transcription and transporter functions of OCTN1 and OCTN2 and
increase risk for CD with an odds ratio between 3.4 and 5.1 in homozygotes. 52 The
OCTN mutations also interact with CARD15, another gene associated with CD, to
increase the risk of CD, with an odds ratio between 7.2 and 10.5 compared to the
control population. 52
Lamhonwah et al. 53 speculated that the human OCTN3 protein, whose correspond-
ing gene is not yet cloned, may also be involved in the etiology of CD. In a recent
study, the same group 54 have hypothesized that an amino acid epitope is shared by
the OCTN1 variant with Campylobacter jejuni and Mycobacterium paratuberculosis ,
which would cross-react in the presence of enterocolitis and cause an impairment of
mitochondrial -oxidation to initiate IBD. Martinez et al. 55 have examined the asso-

ciation of the OCTN genes with CD in a case-controlled study in a Spanish cohort.
Their data support the hypothesis of certain polymorphisms in the SLC22A4 and
SLC22A5 as genetic markers of susceptibility/protection for CD.
Recently, Waller et al. 56 reported that OCTN variants were as strongly associ-
ated with ulcerative colitis (UC) as they were with CD. OCTN variants were in tight
linkage disequilibrium with the extended IBD5 risk haplotypes. OCTN substrates
including carnitine, butyrylcarnitine, and propionylcarnitine have been documented
to have an important effect in the gut. 57 The colonic epithelium is principally nour-
ished by short-chain fatty acids, particularly butyrate. 58 Butyrate, produced in the
colon by bacterial breakdown of dietary fiber, has beneficial effects on the colon,
and butyrate enemas decrease colon inflammation in IBD. 59 Many mechanisms for
butyrate's suppression of inflammation have been described. 60 - 62 Whatever the mech-
anism, OCTNs may be implicated, as butyrate is transported as butyrylcarnitine by
OCTN1 and OCTN2. 9 , 18 The link with autoimmune disorders has been further sup-
ported by studies showing that OCTN genes are also associated with rheumatoid
arthritis. 63

3.4. REGULATION OF CARNITINE TRANSPORTERS

There are very few reports regarding the regulation of OCTN transporters. Stephens
et al. 64 showed that plasma insulin levels have a regulatory effect on OCTN2 tran-
scription. This finding is in accordance with the hypothesis that insulin can augment
Na + -dependent skeletal muscle carnitine uptake, secondary to its action of increasing
sarcolemmal Na + /K + -ATPase pump activity, and thus intracellular Na + flux. 65 The
Na + -dependent active transport of carnitine into human skeletal muscle is mediated
via the high-affinity OCTN2. An additional novel finding from this study was that the
combination of hypercarnitinemia and hyperinsulinemia increased OCTN2 mRNA
expression, whereas hypercarnitinemia alone appeared to have no effect. Whether the
increase in OCTN mRNA expression was the result of the increase in intracellular
total carnitine content or the elevated serum insulin concentration requires further
investigation. Nevertheless, these findings suggest that OCTN2 is regulated at the
transcriptional level, which presents another possible target for increasing muscle
carnitine stores.