Organic Anion Transporters Oat Slc22A Oatp Slco

Conventional pH-partition hypothesis theory states that ionic agents generally exhibit low passive membrane permeability, resulting in their poor bioavailabil-ity. However, there is evidence demonstrating that the intestinal absorption of numerous ionic agents are mediated by the organic anion (OA) or organic cation (OC) transporter systems (Katsura and Inui, 2003; Sai and Tsuji, 2004; Steffansen et al., 2004), thereby overcoming the passive membrane barriers and significantly increasing the intestinal absorption of these compounds (Table 7.7). The expression and function of a variety of these transporters have been investigated; however, their ability to mediate transport of ionic drugs across the intestinal epithelium is still poorly understood. This section will briefly describe the most recent studies involving the role of the OA (Sect. 7.3.2) and OC (Sect. 7.3) families in the mediation of intestinal absorption. Several comprehensive review articles on these transporter families are suggested for additional information (Hagenbuch and Meier, 2003; Koepsell et al., 2003; Tirona and Kim, 2002; van Montfoort et al., 2003; Jonker and Schinkel, 2004; Koepsell and Endou, 2004; Miyazak etal., 2004; You, 2004).

According to the pH-partition hypothesis, most anionic drugs are expected to traverse the intestinal epithelium by passive diffusion in the nonionized state, due to the presence of an acidic microclimate around the intestinal epithelial cells. However, involvement of specific anion transporters in the intestinal absorption of anionic compounds has also been suggested (Katsura and Inui, 2003; Mizuno et al., 2003; Kunta and Sinko, 2004; Sai and Tsuji, 2004; Steffansen et al., 2004). The organic anion transporters are classified into several categories: organic anion transporters (OATs), organic anion transporting polypeptides (rodents: Oatps; human: OATPs), and multiple drug resistance-associated proteins (MRPs) (Hagenbuch and Meier, 2003; van Montfoort et al., 2003; Miyazak et al., 2004; Koepsell and Endou, 2004).

Table 7.7. Organic cation and anion transporters in human instestine

Name

Transport mode

Endogenous substrates

Xenobiotics/drugs

Organic cation transporters hOCT1

(SLC22A2a)

hOCT2 (SLC22A2)

hOCT3 (SLC22A3)

Organic cation/cartine transporters hOCTN2 (SLC22A5)

Organic anion transporting polypeptides OATP-B (SLC21A9)

OATP-D

(SLC21A11) OATP-E (SLC21A12)

ND ND

Prostaglandin E2, F2

Choline, histamine, dopamine, serotonin, noradrenaline, agmatine,

Prostaglandin E2, F2 Serotonin, adrenaline, noradrenaline, agmatine

Acetyl-L-carnitine, L-carnitine, D-carnitine

Prostaglandin E2

Prostaglandin E2, estrone sulfate Taurocholate, thyroid hormones, prostaglandin, estrone sulfate,

TEAc, MPP+, N-methylquinine, N-methylquinidine, tributylmethylammonium, Acyclovir, ganciclovir TEA, MPP+,

N-methylnicotinamide, cimetidine amantadine, memantine

MPP+ , cimetidine

TEA, quinidine, pyrilamine, verapamil

Estrone sulfate, BSP, fexofenadine, pravastatin, temocaprilat Benzylpenicillin a Solute carrier family gene symbol b C, cotransporter; E, exchanger; F, facilitated transporter c TEA, tetraethylammonium; MPP+, 1-methyl-4-phenylpyridium; PAH, p-aminohippuric acid; BSP, bromosulfophthalein, DHEAS, dehydroepiandrosterone sulfate b

To date, five structurally related isoforms (OAT1-5) have been identified in the OAT family (Miyazak et al., 2004; You, 2004). Most OAT isoforms are predominantly expressed in the kidney and have important functions in renal clearance of relevant substrates (Miyazak et al., 2004), although rat OAT2 was expressed at much higher level in liver compared to kidney (Sekine et al., 1998). In contrast to the liver and kidney, OATs are expressed to a lesser extent, in brain, muscle, eye, and placenta (Miyazak et al., 2004). The distribution patterns of OAT family members might be one of the important determinants influencing the substrate's phar-macokinetics. OAT family members share some common topology characteristics including twelve a-helix TMD; one large hydrophilic extracellular loop between TMD 1 and 2 carrying several potential glycosylation sites; and a large intracellu-lar loop containing multiple potential phosphorylation sites between TMD 6 and 7 (You, 2004).

OATs are polyspecific transporters that are capable of interacting with a wide range of clinically significant organic anion drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), p-lactam antibiotics, antiviral drugs, diuretics, antitumor drugs, and angiotensin-converting enzyme inhibitors (Koepsell and Endou, 2004; You, 2004). While OAT isoforms have broad substrate specificity, members of the OAT family have not been identified in the human intestine. In fact, the intestinal expression of OAT members is quite limited, with only one report demonstrating the presence of OAT2 mRNA in mouse fetal intestine (Pavlova et al., 2000). In contrast to the abundance of members of the MRP family identified in the intestine, the role of the OAT family in the intestinal absorption of drugs seems to be negligible and will not be discussed further.

The related OATP/Oatp isoforms are part of a rapidly expanding family of mammalian transporters that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds (Hagenbuch and Meier, 2003; Tirona and Kim, 2002; van Montfoort et al., 2003). The OATP/Oatp genes were previously classified within the solute carrier family 21A (SLC21A) and were given various trivial names (Hagenbuch and Meier, 2004; Mikkaichi et al., 2004). However, this classification does not provide a clear and species independent identification of genes. Therefore, in agreement with the HUGO Gene Nomenclature Committee (HGNC), all OATP/Oatp isoforms are currently classified within the OATP/SLCO superfamily based on their putative phylogenetic relationships and the chronology of identification (Hagenbuch and Meier, 2004; Mikkaichi et al., 2004; http://www.bioparadigms.org/slc/SLC21.htm). Of the 52 members of the OATP/SLCO superfamily, 36 isoforms have been identified across the human, rat, and mouse genomes. The OATP/SLCO isoforms are identified within six out of 13 subfamilies (OATP1-OATP6) having different structural features as compared with OATs. While possessing twelve TMD, OATP/SLCO iso-forms contain a large extracellular domain between TMD 9 and 10 (extracellular loop 5) and have multiple glycosylation sites in extracellular loop 2 and 5. In addition, there is an OATP superfamily signature (D-X-RW-(I,V)-GAWW-X-G-(F,L)-L.) at the border between extracellular loop 3 and TMD 6 (Hagenbuch and Meier, 2003).

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