ORGANIC CATION/CARNITINE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 42

deficiency syndromes are generated by the inhibition of carnitine transport by drugs
that use the same transporters. 44
3.3.1. Primary Systemic Carnitine Deficiency
Patients affected by homozygous mutations in OCTN2 gene are severely symptomatic
due to the resulting cardiomyopathy, progressive skeletal weakness, nonketotic hypo-
glycemia, and hyperammonemia. Many mutations in the OCTN2 protein have been
identified, as, reviewed by our laboratory. 1 The impairment of fatty acid oxidation,
particularly during fasting, can also have negative effects on skeletal, muscular, car-
diac, and liver function in heterozygotes. 45
Mutations and Single Nucleotide Polymorphisms Lahjouji et al. 1 summarized the
OCTN2 mutations described up until 2001. These are classified as nonsense and
missense mutations, presenting the specific genotype, ethnicity, gender, and age of
the patients with consanguinity and the clinical manifestations. Affected patients are
from different ethnic origins, and the majority of cases are present during infancy.
Both missense and nonsense mutations are known. The missense mutations can also
be classified into those that abolish carnitine transport entirely and those that reduce
transport to residual activity. A list of single-nucleotide polymorphisms is also
provided. 1
Juvenile Visceral Steatosis Mouse The JVS phenotype is inherited in an autosomal
recessive manner. Localization of the mutation has been determined with molecular
genetic studies using detailed chromosome linkage analysis and positional cloning as
within a 1.6 cM (centiMorgan) region on mouse chromosome 11. This corresponds
to the OCTN2 region on human chromosome 5q31. 5 Lu et al. 31 have isolated the
mouse Octn2 gene and identified the mutation in the JVS mouse to be L352R. This
mutation is located in the middle of the putative seventh transmembrane domain of
Octn2 in the JVS mouse. 32 The hydrophobic residue (L) in a membrane-spanning
region is predicted to disturb topology that is essential for function. Yokogawa et
al. 46 have compared the characteristics of L-carnitine transport in isolated hepato-
cytes from wild-type and JVS mice. The uptake of carnitine in controls was saturable
and showed two distinct components, high and low affinity. The high-affinity up-
take, which showed properties similar to those of Octn2, was absent in JVS hep-
atocytes. All these results indicate that JVS mice represent a valid animal model
for human primary carnitine deficiency. Functional and molecular studies have es-
tablished that the JVS mice phenotype is caused by mutations in the high-affinity
OCTN2.
3.3.2. Drug Inhibitors and Secondary Carnitine Deficiency
Tein, 44 in an excellent review, has discussed the inhibition of carnitine uptake by a
large number of xenobiotics that are in extensive clinical use, including lipophilic
organic cations (quinidine, verapamil, and emetine) and zwitterionic compounds