Functions of OATP1A and 1B transporters in vivo: insights from mouse models

Iusuf, Dilek; Steeg, Evita van de; Schinkel, Alfred H.

doi:10.1016/j.tips.2011.10.005

Cited by 69 publications

(75 citation statements)

References 59 publications

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“…Another issue that should be considered is the possible species difference between mice and humans. Intestinal expression of functional murine Oatp2b1 is not fully understood, but available evidence suggests that Oatp2b1 is expressed in mouse enterocytes and contributes to intestinal absorption of xenobiotics and drugs (Cheng et al, 2005;Iusuf et al, 2012). Accordingly, we consider that Oapt2b1 is functional in mice similarly to OATP2B1 in humans and that consequently the present observations can be extrapolated to humans.…”

Section: Discussionmentioning

confidence: 67%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP) 1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial b-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora.

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Section: Discussionmentioning

confidence: 67%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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“…OATPs are a superfamily of transport proteins responsible for sodiumindependent uptake of compounds that include hormones, bile salts, xenobiotics, and drugs Meier, 2003, 2004;Iusuf et al, 2012;Hagenbuch and Stieger, 2013). The superfamily is composed of six families based on 40% amino acid sequence identity divided into subfamilies that have 60% amino acid homology (Iusuf et al, 2012;Hagenbuch and Stieger, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…The superfamily is composed of six families based on 40% amino acid sequence identity divided into subfamilies that have 60% amino acid homology (Iusuf et al, 2012;Hagenbuch and Stieger, 2013). OATP family members are expressed in multiple organs, including the brain, heart, kidney, intestine, and liver, and they share structural similarities that include predicted 12 transmembrane domains (Wang et al, 2008;Hagenbuch and Stieger, 2013) and 3-4 N-linked glycosylation sites (Wang et al, 2008;Yao et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Oatp1a1 Requires PDZK1 to Traffic to the Plasma Membrane by Selective Recruitment of Microtubule-Based Motor Proteins

2013

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Previous studies identified a family of organic anion transport proteins (OATPs), many of which have C-terminal PDZ binding consensus sequences. In particular, the C-terminal four amino acids of Oatp1a1, a transporter on rat and mouse hepatocytes, comprise a consensus binding site for PDZK1. In PDZK1 knockout mice and in transfected cells where PDZK1 expression was knocked down, Oatp1a1 accumulates in intracellular vesicles. The present study tests the hypothesis that Oatp1a1 traffics to and from the cell surface in vesicles along microtubules, and that PDZK1 guides recruitment of specific motors to these vesicles. Oatp1a1-containing vesicles were prepared from wild-type and PDZK1 knockout mice. As seen by immunofluorescence, kinesin-1, a microtubule plus-end directed motor, was largely associated with vesicles from wildtype mouse liver, whereas dynein, a minus-end directed motor, was largely associated with vesicles from PDZK1 knockout mouse liver. Quantification of motility on directionally marked microtubules following addition of 50 mM ATP showed that wild-type vesicles moved equally toward the plus and minus ends whereas PDZK1 knockout vesicles moved predominantly toward the minus end, consistent with net movement toward the cell interior. These studies provide a novel mechanism by which PDZK1 regulates intracellular trafficking of Oatp1a1 by recruiting specific motors to Oatp1a1-containing vesicles. In the absence of PDZK1, Oatp1a1-containing vesicles cannot recruit kinesin-1 and associate with dynein as a predominant minus-end directed motor. Whether this is a result of direct interaction of the Oatp1a1 cytoplasmic domain with dynein or with a dynein-containing protein complex remains to be established.

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“…Several OATPs capable of transporting bile acids are expressed in the small intestine (OATP1A2 and OATP2B1 in humans; Oatp1a4, Oatp1a5, and Oatp2b1 in mice) ( 48,49 ), and their role in transporting xenobiotics and endobiotics such as bile acids has been examined recently using OATP-null mouse models ( 13, 50 ). In mice engineered to delete the entire Oatp1a/ 1b locus (encompassing Slco1b2 , Slco1a4 , Slco1a1 , Slco1a6 , and Slco1a5 ), plasma levels of conjugated bile acids were unchanged, whereas unconjugated bile acid levels increased by approximately 13-fold ( 13 ).…”

Section: Intestinal Apical Brush Border Membrane Transportmentioning

confidence: 99%