Polymorphisms in Human Organic Anion-transporting Polypeptide 1A2 (OATP1A2)

Abstract

Organic anion-transporting polypeptide 1A2 (OATP1A2) is a drug uptake transporter known for broad substrate specificity, including many drugs in clinical use. Therefore, genetic variation in SLCO1A2 may have important implications to the disposition and tissue penetration of substrate drugs. In the present study, we demonstrate OATP1A2 protein expression in human brain capillary and renal distal nephron using immunohistochemistry. We also determined the extent of single nucleotide polymorphisms in SLCO1A2 upon analyses of ethnically defined genomic DNA samples (n ‫؍‬ 95 each for African-, Chinese-, European-, and Hispanic-Americans). We identified six nonsynonymous polymorphisms within the coding region of SLCO1A2 (T38C (I13T), A516C (E172D), G559A (A187T), A382T (N128Y), A404T (N135I), and C2003G (T668S)), the allelic frequencies of which appeared to be ethnicitydependent. In vitro functional assessment revealed that the A516C and A404T variants had markedly reduced capacity for mediating the cellular uptake of OATP1A2 substrates, estrone 3-sulfate and two ␦-opioid receptor agonists, deltorphin II, and [D-penicillamine 2,5 ]-enkephalin. On the other hand, the G559A and C2003G variants appeared to have substrate-dependent changes in transport activity. Cell surface biotinylation and immunofluorescence confocal microscopy suggested that altered plasma membrane expression of the transporter may contribute to reduced transport activity associated with the A516C, A404T, and C2003G variants. The A404T (N135I) variant also showed a shift in the apparent molecular size, indicative of alterations in glycosylation status. Taken together, these data suggest that SLCO1A2 polymorphisms may be an important yet unrecognized contributor to interindividual variability in drug disposition and central nervous system entry of substrate drugs.During the past decade, there has been an increasing recognition of the critical interplay between drug transporters and drug-metabolizing enzymes as determinants of drug disposition and response. Indeed, the extent of targeted tissue entry for many drugs may be facilitated by drug transporters, which are often expressed in a tissue-specific manner with broad substrate specificities. Among the uptake transporters, members of the organic anion-transporting polypeptides (human, OATPs 1 ; rodents, Oatps) have been shown to be expressed in organs such as the central nervous system, liver, and intestine and mediate the cellular uptake of a large number of structurally divergent compounds (1). Within this family, OATP1A2 (SLCO1A2, also known as human OATP-A or OATP1) was the first human OATP to be cloned and characterized (2). OATP1A2 mRNA has been detected in various tissues including the brain, liver, and kidney (2, 3). Substrates of OATP1A2 include endogenous compounds such as bile acids, steroid hormones, and their conjugates, thyroid hormones, as well as drugs including fexofenadine, ouabain, peptides (e.g. deltorphin II, [D-penicillamine 2,5 ]enkephalin, DPDPE), and the toxin, microcystin (2, ...

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…In this study, SLCO1A2 genotyping was not performed because SNPs that affect OATP1A2 transport activity are not typically found in the Asian population. 46 Consequently, the disposition of IM may be altered by ABCG2 421C4A, such that polymorphism-dependent differences in IM trough concentration reflect a difference in hepatic IM biliary excretion rather than a difference in intestinal IM absorption.…”

Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

“…However, some members show a tissuespecific distribution; OATP1B1 and OATP1B3 are exclusively expressed in liver (Hsiang et al 1999, Konig et al 2000, whereas OATP1C1 is only present in the brain and in the Leydig cells of the testis (Pizzagalli et al 2002). Furthermore, most OATP family members are expressed at the basolateral membrane of polarized cells (Hsiang et al 1999, Konig et al 2000, Lee et al 2005.…”

“…Two common (Ile13Thr and Glu172Asp) and two rare (Arg168Cys and Asn278X) protein-altering variants of OATP1A2 showed altered transport function. In a different study, Glu172Asp and Asn135Ile variants showed markedly reduced transport of the OATP1A2 substrates estrone sulfate (E1S) and deltorphin II (Lee et al 2005). Other variants (Ala187Thr and Thr668Ser) appeared to have substrate-dependent changes in transport activity (Lee et al 2005).…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…All the intestinal transporters for organic anions are also expressed in human hepatocytes more or less, although ASBT, OATP1A2 and MRP1 appear not to be present in these cells, and little seems to be known about the expression of hepatic MCTs. [50][51][52] However, several additional transporters are expressed in the liver. The majority of these are mainly transporters for organic anions, i.e.…”

“…Bilirubin [143] Chenodeoxycholate [144] Chlorambuciltaurocholate [145] Dexamethasone [146] Cholate [144] 93 Cholate [144] Ciprofloxacin [147] Ciprofloxacin [147] DHEAS [40,146] 6.6 E217bG [146] Enoxacin [147] Enoxacin [147] E217bG [40,143] Estrone-3-sulfate [146] Fexofenadine [19,148] 6.4 Erythromycin [148] Estrone-3-sulfate [40,51,149] 16/59 3-Iodothyronamine [150] Gatifloxacin [147] Grepafloxacin [147] Glycocholate [40,144] Taurochenodeoxycholate [144,146,149] Imatinib [151] Indinavir [148] Prostaglandin E2 [40] Levofloxacin [147] 136 Ketokenazole [148] Reverse triiodothyronine [38] Taurocholate [144] Lomefloxacin [147] Lovastatin [148] Taurochenodeoxycholate [144] Tauroursodeoxycholate [144,146] Methotrexate [152] 457 Moxifloxacin [147] Taurocholate [40,…”