期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 106, 期 9, 页码 2412-2419出版社
WILEY
DOI: 10.1016/j.xphs.2017.05.017
关键词
biliary excretion; in vitro models; toxicology; bile acid transporters; efflux pumps
资金
- Japan Society for the Promotion of Science KAKENHI grant [JP26460190]
- Grants-in-Aid for Scientific Research [17J03861] Funding Source: KAKEN
Inhibition of bile salt export pump (BSEP) causes hepatic accumulation of toxic bile acid (BA), leading to hepatocyte death. We reported a sandwich-cultured hepatocyte (SCH)-based model that can estimate potential cholestatic compounds by assessing their ability to induce hepatotoxicity in combination with a titrated amount of human 12 BA species. However, there is little information about the specific BAs responsible for hepatotoxicity, when BSEP is inhibited. This study measured the accumulation of each BA in rat SCHs in the presence of 10 mu M cyclosporine A (CsA), which only inhibits BSEP, and 50 mu M CsA, which further inhibits basolateral BA efflux transporters. The accumulation of all BAs (not significant for deoxycholic acid [DCA]) was observed in the presence of 10 mu M CsA. In particular, 3 BAs (chenodeoxycholic acid [CDCA], DCA, and glyco-DCA [GDCA]) showed increased toxicity in the presence of 10 mu M CsA, whereas the other BAs did not. In addition to these BAs, taurolithocholic acid, glyco-CDCA, and glycocholic acid showed increased toxicity in the presence of 50 mu M CsA, but additional accumulation of these BAs could not be observed. These results indicate the inhibiting BSEP results in the accumulation of CDCA, GDCA, and partially DCA, thereby resulting in hepatotoxicity. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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