ORGANIC ANION–TRANSPORTING POLYPEPTIDES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 77

has not prevented some inadvertent comparisons of nonhomologous Oatps among
humans and rodents. 6 , 7
Allelic variants of OATPs are often named based on haplotype analysis and given
a chronologically determined numerical designation after the “star” symbol “ ∗ ” (e.g.,
OATP1B1 ∗ 15), where typically, ∗ 1 represents the reference allele. At present, an
allelic nomenclature committee for OATPs has not been established similar to one
organized for the CYP enzymes. 8 Hence, a standardized OATP allelic nomenclature
as assigned by a formal committee is required in the promotion of human transporter
genetics.
5.2. MOLECULAR CHARACTERISTICS OF OATPs
5.2.1. Gene Structure
The human OATPs are encoded by the SLCO genes located on a number of different
chromosomes (Table 5.1). Members of the SLCO1 family are found in a gene locus
on chromosome 12, including a pseudogene related to the SCLO1B subfamily. 9 The
SLCO genes span from 30 to 310 kb in length and consist of 10 to 18 exons (Table
5.1). In silico analysis (www.genecards.org) predicts that many of the human OATPs
are expressed as splice variants (Table 5.1), but experimental verification, tissue dis-
tribution, and functional assessment of such isoforms remains lacking. Functional
splice variants of rodent Oatp1a3 have been described. 10 , 11
5.2.2. Protein Structure
The OATPs are predicted to represent integral membrane proteins that contain 12
transmembrane (TM) helices that harbor the characteristic superfamily signature
amino acid sequence D-X-RW-(I,V)-GAWW-X-G-(F,L)-L. 1 Amino and carboxy ter-
mini are oriented to the cytoplasmic spaces. Predicted and confirmed N-glycosylation
sites are found, many conserved between transporters, in extracellular loops 2 and
5 (see below). Little is known regarding the tertiary structures of OATPs, although
more recent studies are beginning to address this aspect of OATP biology. In silico,
structural modeling studies with OATP1B3 and OATP2B1 have suggested that the
OATPs share features of the major facilitator superfamily (MFS). 3 In these models,
OATP1B3 is predicted to possess a central pseudo twofold symmetry axis perpen-
dicular to the membrane plane and a central pore. The pore formed by TM helices
1, 2, 4, 5, 7, 8, 10, and 11 contains conserved basic/polar residues thought to be
important to substrate binding and transport mechanisms. 3 Experimental support of
the functional importance of these pore residues would be of interest. In addition,
modeling of the large extracellular loop 5 in OATP1B3 revealed similarities to Kazal-
type serine protease inhibitors and predicted internal disulfide bonds of the present
cysteine residues. 3 The relevance of the 10 cysteine residues in the fifth extracel-
lular loop of OATP2B1 was examined by mutational analysis. 12 Indeed, mutation
of any of the cysteine residues or deletion of the loop itself caused mistrafficking