ORGANIC CATION/CARNITINE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 36

3.1. INTRODUCTION

Carnitine (3-hydroxy-4- N -trimethylaminobutyric acid), a zwitterion, is an essential
cofactor in the metabolism of lipids and consequently in the production of cellu-
lar energy. L-Carnitine, the active form, has important physiological roles, including
involvement in the

-oxidation of fatty acids, facilitation of the transport of long-
chain fatty acids across the mitochondrial inner membrane as acylcarnitine esters,
and modulation of intracellular coenzyme A homeostasis. 1 It is involved in transfer

of the products of peroxisomal -oxidation to mitochondria. In humans, L-carnitine

is obtained from dietary sources, primarily meat and dairy products, and produced
endogenously from the amino acids lysine and methionine, with both sources con-
tributing to plasma and tissue levels.
The major site of carnitine absorption is the small intestine, but the mechanism of
intestinal uptake of L-carnitine is unclear. Previous studies using Caco-2 cells demon-
strated that the transport of L-carnitine involved a carrier-mediated system. 2 Results
from our laboratory showed that L-carnitine uptake in differentiated Caco-2 cells was
mediated primarily by the organic cation/carnitine transporter OCTN2, located on
the brush border membrane. 3 Carnitine is eliminated as free carnitine or acylcarnitine
almost exclusively by the kidney, which plays a crucial role in homeostatic regu-
lation of carnitine concentrations in body fluids. Carnitine reabsorption appears to
be regulated such that normal plasma carnitine concentration is maintained without
significant loss of carnitine in the urine. Although there is evidence of different po-
larized carnitine transporters in the kidney, the brush border membrane transporter
is probably OCTN2, as indicated by a strong reactivity with the anti-OCTN2 poly-
clonal antibody. 4 There is considerable evidence that various organic cation/carnitine
transporters may be involved in carnitine distribution, and organic cation absorption
and elimination in several tissues. 5
The organic cation/carnitine transporters are a subgroup of the SLC22 (solute car-
rier) drug transporter family, which belongs to the major facilitator superfamily. 6 This
superfamily comprises uniporters, symporters, and antiporters from bacteria, lower
eukaryotes, plants, and mammals. In human species and mammals, they participate
in the absorption and/or excretion of drugs, xenobiotics, and endogenous compounds
in the intestine, liver, and/or kidney, and perform homeostatic functions in brain and
heart. Various subgroups of the SLC22 drug transporter family are discussed in de-
tail in other chapters of this topic. In the present chapter, the discussion focuses on
the known members of the organic cation/carnitine transporter (OCTN) subgroup
and related carnitine transporters. Emphasis is on the clinical importance of OCTN
transporters. Primary systemic carnitine deficiency (SCD) and secondary L-carnitine
deficiency syndromes known to be related to OCTN levels and expression lead to
a reduced use of fatty acids in energy production. SCD is an autosomal recessive
disorder caused by mutations in the gene encoding for the Na + /L-carnitine trans-
porter OCTN2. 1 Recently, two variants in the OCTN1 and OCTN2 genes have been
shown to exist in a haplotype, which is associated with a susceptibility to Crohn's
disease. 7