Ct2

L-Carnitine

Facilitator

Testis

Uptake

CT, carnitine transporter; EMT, extraneuronal monoamine transporter.

the extracellular loops 2 and 5, and the OATP 'superfamily signature' at the border between extracellular loop 3 and TMD6 (Figure 6); 13 rat, 11 mouse, and 11 human Oatps/OATPs have been identified to date. The amino acid contents of the mammalian proteins are 31-82% identical, and these similarities have been used to arrange individual proteins into families and subfamilies. The amino acid profiles of the rat, mouse, and human OATP-3 proteins (r Oatp11, m Oatp11, and OATP3A1) are almost identical (97% and 98%).12

The OATPs were originally characterized as uptake transporters, although some may function primarily for efflux.74 The driving force for OATP-mediated transport is still not clear, but it is independent of ATP or sodium gradients. There is experimental evidence that bidirectional transmembrane transport can be mediated by anion (HCO3—) or GSH exchange. The GSH gradient may be a powerful driving force. It is due to the high intracellular GSH concentration (approximately 10 mM), the low extracellular concentration (approximately 0.01 mM), the negative charge on GSH at physiological pH, and the negative intracellular potential ( — 30 to — 60 mV). This is well documented for rat Oatp 1 and Oatp 2, but many other OATPs remain to be checked. Oatp 1 (Oatp1a1) was first cloned as a bromosulfophthalein (BSP) and taurocholate uptake system of the rat liver. It has now been shown that many OATPs are polyspecific OATs with partially overlapping substrate specificities for a wide range of solutes, including bile salts, organic dyes (BSP), steroid conjugates (DHEAS, 17^E2G estrone-3-sulfate (E-3-S)), thyroid hormones, neuroactive peptides ((D-penicillamine-2,5) enkephalin (DPDPE), Leu-enkephalin and deltorphin II), and numerous drugs and toxins such as the cardiotonic digoxin, the angiotensin-converting enzyme inhibitors enalapril and temocaprilat, and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin (Table 2). OATP substrates are mainly high molecular weight (>450 Da) amphiphatic molecules, mostly bound to albumin, that have a steroid nucleus or linear and cyclic peptides.76 Most OATPs, mainly those of the OATP1 family, are found in many tissues and though to be part of the overall body detoxification system, helping to remove xenobiotics from the systemic circulation (e.g., drug uptake into hepatocytes). Others, those of families 2-4, may act more specifically in selected organs, such as transporting thyroid hormones or steroids. The rat Oatp1a1, Oatp1a4, and Oatp1b2, and human OATP1B3, OATP1B1, and OATP2B1 are found in the sinusoid membrane of hepatocytes, where they are responsible for the uptake of xenobiotics for hepatic clearance. The hepatic OATPs may have a strategic role in

Table 4

Current human OAT protein, SLC22 gene nomenclature and properties

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