ORGANIC CATION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 27

2.7.3. OCT3

In a study of genetic variation in 26 membrane transporter genes in a large sample ( n =

247) of ethnically diverse human subjects, Leabman et al. discovered 14 nucleotide
substitutions in OCT3. 76 The survey region included the exons and flanking intronic
region. Of the 14 variants identified, five were located in the coding exonic regions,
and three of these (Thr44Met, Ala116Ser, and Thr400Ile) resulted in a change in the
amino acid sequence. Only Ala116Ser was polymorphic, with an allele frequency of
1.7% in the African-American subset of the sample. These variants have not been
tested for effects on OCT3 function.
Genetic variation in OCT3 was investigated independently by resequencing the
core promoter, exons, and 3 untranslated region of the gene in 100 healthy persons
of European descent. 77 Six nucleotide substitutions and one single base pair deletion
were discovered, including G in the OCT3 promoter and three synonymous

substitutions in the coding region. The functional consequences of these variants have
not been studied. The authors suggest that the synonymous 1233G

− 29A >

> A substitution

may generate a cryptic 3 -splice acceptor site.
Additional data on genetic variation in organic cation transporter genes are avail-
able on online public databases. The Pharmacogenetics and Genomics Knowledge
Base (PharmGKB, www.pharmgkb.org) is a repository for data and information re-
lated to all areas of pharmacogenetics. PharmGKB includes well-annotated pages de-
scribing genetic variation in OCTs, identified by the Pharmacogenetics of Membrane
Transporters project (PMT, www.pharmacogenetics.ucsf.edu) in a large collection
of DNA samples from ethnically diverse populations. The NCBI single-nucleotide
polymorphism database (dbSNP, www.ncbi.nlm.nih.gov/SNP/) also includes data on
OCT variants. The HapMap project (www.hapmap.org), which aims to take advan-
tage of linkage between SNPs to increase power in genetic association studies, may
prove to be a useful tool for studying the genetics of response to OCT substrates.

2.8. CONCLUSIONS

The OCTs are a fairly well-studied family of multispecific organic cation transporters,
with potential influence for a large number of endogenous and pharmacological com-
pounds. The tissue distribution and subcellular localization of these transporters sug-
gest that their primary role is in the excretion of toxic xenobiotic and endogenous
organic cations. OCT1 is a hepatic sinusoidal uptake transporter and appears to be most
important for drug distribution into liver, where it aids in presentation of substrate
drugs to hepatic metabolizing enzymes or in biliary excretion. OCT2, the kidney-
specific organic cation transporter, is primarily responsible for basolateral uptake of
organic cations into renal proximal tubules and acts as the first step in active tubular
secretion of its substrates. OCT3 has a more diffuse pattern of expression, as well as a
relatively unique substrate selectivity profile, and is thought to be important for extra-
neuronal clearance of monoamine neurotransmitters as well as uptake of monoamines
into the heart and across the placenta. Knockout mouse models of the OCTs have