In vitro bile acid-dependent hepatocyte toxicity assay system using human induced pluripotent stem cell-derived hepatocytes: Current status and disadvantages to overcome. Issue 4 (August 2019)

• Record Type: Journal Article
• Authors: Sakai, Yoko; Iwao, Takahiro; Susukida, Takeshi; Nukaga, Takumi; Takemura, Akinori; Sekine, Shuichi; Ito, Kousei; Matsunaga, Tamihide
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 34:Issue 4(2019)
• Page Start: 264
• Page End: 271
• Publication Date: 2019-08
• Subjects: Bile acid -- Cholestatic drug-induced liver injury -- Human induced pluripotent stem cell -- Multidrug resistance-associated protein -- Sandwich-cultured hepatocyte model; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2019.04.004
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: Cholestatic drug-induced liver injury (DILI) is a type of hepatotoxicity. Its underlying mechanisms are dysfunction of bile salt export pump (BSEP) and multidrug resistance-associated protein 2/3/4 (MRP2/3/4), which play major roles in bile acid (BA) excretion into the bile canaliculi and blood, resulting in accumulation of BAs in hepatocytes. The sandwich-cultured hepatocyte (SCH) model can simultaneously analyze hepatic uptake and biliary excretion. Therefore, we investigated whether sandwich-cultured human induced pluripotent stem cell (iPS cell)-derived hepatocytes (SCHiHs) are suitable for evaluating cholestatic DILI. Fluorescent N-(24-[7-(4-N, N-dimethylaminosulfonyl-2, 1, 3-benzoxadiazole)]amino-3α, 7α, 12α-trihydroxy-27-nor-5β-cholestan-26-oyl)-2′-aminoethanesulfonate (tauro-nor-THCA-24-DBD, a BSEP substrate) was accumulated in bile canaliculi, which supports the presence of a functional bile canaliculi lumen. MRP2 was highly expressed in the Western blot analysis, whereas the mRNA expression of BSEP was hardly detectable. MRP3/4 mRNA levels were maintained. Of the 22 compounds known to cause DILI with BAs, 7 showed significant cytotoxicity. Most high-risk drugs were detected using the developed SCHiH system. However, a shortcoming was the considerably low expression level of BSEP, which prevented the detection of some relevant drugs whose risks should be detected in primary human hepatocytes. Graphical abstract: Image 1