Biomedical Engineering Reference
In-Depth Information
5.1. OVERVIEW OF THE OATP SUPERFAMILY
5.1.1. Introduction
The study of drug transport across biological membranes has gathered considerable
attention over the last decade as a result of rapid advances in genetic and molecular
biological tools that promoted the elucidation of the responsible transporter pro-
teins. Among the most widely investigated transport proteins are the organic anion-
transporting polypeptides (OATPs). These proteins are characteristically known for
their sodium-independent transport of substrates with broad specificity. Interest in the
OATPs continues to grow due to the cumulative evidence gathered from in vitro and
in vivo studies that demonstrate important roles for these transporters in determining
intestinal drug absorption, hepatic and renal clearance, and tissue distribution.
In this chapter we begin with a review of the OATP superfamily nomenclature,
followed by sections covering molecular characteristics, aspects of gene expression
and regulation, transport substrates and inhibitors, and relevance to pharmacology
and physiology. Specific attention is focused on members of the human OATP family,
although illustrations with nonhuman Oatps are noted where relevant. Readers are also
directed toward several general reviews
1
−
3
and chapters in this topic that cover in
greater detail elements of OATPs in various species.
5.1.2. Nomenclature
For several years after the discovery of the first Oatp,
4
the rapid identification of new
members of the transporter superfamily in various species along with the various
naming systems was a source of confusion for those who were not closely following
the field. It remained difficult to determine the relatedness and identities of the Oatps
within and between species until the new classification and nomenclature was de-
veloped by Hagenbuch and Meier
2
and approved by the HUGO Gene Nomenclature
Committee. In this system, Oatps are classified according to conventions originally
established for the cytochrome P450 (CYP) enzyme superfamily,
5
which are based on
amino acid sequence identities. For the Oatps, the italicized gene symbol begins with
Slco
while the encoded proteins are named with the root Oatp. For human genes and
proteins, capitalized letters are used (e.g.,
SLCO
/OATP), whereas for rodents only
the initial letter is in capitals with the rest being in lowercase letters (e.g.,
Slco
/Oatp).
Oatps within the same family that share
40% amino acid sequence identities have
root names followed by Arabic numbers, of which six families are known in humans.
Subfamilies that share
≥
60% amino acid sequence identities are indicated by a letter
following the family designation. For instance, OATP family 1 (OATP1) has three
subfamilies (A, B, and C). Specific transporter proteins are then given numerical
designation after the subfamily heading. Hence OATP1B1 is the first named member
belonging to family 1, subfamily B. The final numeral is named chronologically and
allows for unambiguous identification of Oatp transporters between species. It was
envisioned that this consensus nomenclature would promote standardization and clar-
ity in transporter science. However, despite its introduction, the new nomenclature
≥
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