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Title: 
Pharmacological and Pathophysiological Significance of OATP Transporters

 

Ikumi Tamai,
Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

 

Abstract:
OATP transporter family consists of 11 members and some of them have been studied well as the hepatic drug transporters, since they are selectively expressed in hepatocytes and exhibit broad substrate selectivity. They are well recognized as the responsible transporters for drug-drug interactions (DDI) in liver that cause altered systemic exposures of victim drugs. Accordingly, biomarkers that predict such DDI is useful. We proposed dehydroepiandrosteron sulfate (DHEAS) as the biomarker for DDI on hepatic OATPs1). OATP2B1 contributes to intestinal absorption of orally administered drugs2). Active metabolite of anticancer irinotecan, SN-38 is a substrate of intestinal OATP2B1 and intestinal tissue accumulation of SN-38 via OATP2B1 may contribute to its severe intestinal toxicity, late-onset diarrhea. Since OATP2B1 is affected by fruit juices such as apple juice, taking apple juice during irinotecan therapy might be useful to ameliorate the adverse effect in intestine3). OATPs also have various pathophysiological roles depending on subtypes. Most OATPs transport conjugated metabolites of steroid hormones. For hormone-dependent breast cancer, estrone-3-sulfate (ES), which is present at high concentration in blood even after menopausal, may be taken up by the cancer cells via OATP to facilitate cell growth, since steroid sulfatase is highly expressed in breast cancer cells presumably to metabolize ES to an active estrogen4). Several OATPs such as OATP1B3, 1A2 and 2B1 showed higher expression in breast cancer cells, suggesting they provide estrogen for cell growth. Prostate cancer also exhibits hormone dependence and castration resistance is significant matter for its treatment. We postulated that certain OATPs are overexpressed under androgen depletion and DHEAS is taken up efficiently by the castration resistant cells even in the state of depletion of androgens, since DHEAS is maintained in blood under castration and can be metabolized to an active androgen in the cells. OATP1A2 was overexpressed under androgen depletion, suggesting that OATP1A2 may provide androgen precursor to the cells5). Prostaglandin E2 (PGE2) is involved in many diseases and is a good substrate of OATP2A1. In lung it is expressed in endothelial and pulmonary epithelial cells. Bleomycin-induced lung fibrosis is worsen in oatp2a1-knock out mice6). Since OATP2A1 exhibits highly active and selective transport of PGE2, regulation of PGE2 disposition by OATP2A1 is likely critical for PGs-related diseases. In summary, OATPs are pharmacologically and pathophysiologically interesting transporters and understanding of their exact roles should be useful for better mediactions.

 

References:
1) Watanabe et al., Drug Metab. Pharmacokinet., 30:198-204, 2015. 
2) Tamai & Nakanishi, Curr Opin Pharmacol, 13:859, 2013. 
3) Fujita et al., Drug Metab. Dispos., 44:1-7, 2016.
4) Maeda et al., J. Steroid Biochem Mol Biol 122:180, 2010. 
5) Arakawa et al., Biochem Pharmacol, 84:1070, 2012. 
6) Nakanishi et al., PLoS One, 10(4):e0123895, 2015.