Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics
Abstract An understanding of the quantitative relationship between bile canaliculus (BC) dynamics and the disruption of tight junctions (TJs) during drug‐induced intrahepatic cholestasis may lead to new strategies aimed at drug development and toxicity testing. To investigate the relationship betwee...
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.960 |
| _version_ | 1818202599498711040 |
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| author | Rie Sonoi Yoshihisa Hagihara |
| author_facet | Rie Sonoi Yoshihisa Hagihara |
| author_sort | Rie Sonoi |
| collection | DOAJ |
| description | Abstract An understanding of the quantitative relationship between bile canaliculus (BC) dynamics and the disruption of tight junctions (TJs) during drug‐induced intrahepatic cholestasis may lead to new strategies aimed at drug development and toxicity testing. To investigate the relationship between BC dynamics and TJ disruption, we retrospectively analyzed the extent of TJ disruption in response to changes in the dynamics of BCs cultured with entacapone (ENT). Three hours after adding ENT, the ZO‐1‐negative BC surface area ratio became significantly higher (4.1‐fold) than those of ZO‐1‐positive BCs. Based on these data, we calculated slopes of surface area changes, m, of each ZO‐1‐positive and ZO‐1‐negative BC. BCs with m ≤ 15 that fell within the 95% confidence interval of ZO‐1‐positive BCs were defined as ZO‐1‐positive. To validate this method, we compared the frequency of ZO‐1‐positive BCs, FZ, with that of BCs with m ≤ 15, FT, in culture using drugs that regulate TJ, or induce intrahepatic cholestasis. FT values were correlated with FZ under all culture conditions (R2 = .99). Our results indicate that the magnitude of BC surface area changes is a factor affecting TJ disruption, suggesting that maintaining TJ integrity by slowing BC dilation inhibits cell death. |
| first_indexed | 2024-12-12T03:12:01Z |
| format | Article |
| id | doaj.art-627920d24fa14ac7aae4d2f549c1e6e5 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-12T03:12:01Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-627920d24fa14ac7aae4d2f549c1e6e52022-12-22T00:40:22ZengWileyPharmacology Research & Perspectives2052-17072022-06-01103n/an/a10.1002/prp2.960Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamicsRie Sonoi0Yoshihisa Hagihara1Biomedical Research Institute National Institute of Advanced Industrial Science and Technology Ikeda Osaka JapanBiomedical Research Institute National Institute of Advanced Industrial Science and Technology Ikeda Osaka JapanAbstract An understanding of the quantitative relationship between bile canaliculus (BC) dynamics and the disruption of tight junctions (TJs) during drug‐induced intrahepatic cholestasis may lead to new strategies aimed at drug development and toxicity testing. To investigate the relationship between BC dynamics and TJ disruption, we retrospectively analyzed the extent of TJ disruption in response to changes in the dynamics of BCs cultured with entacapone (ENT). Three hours after adding ENT, the ZO‐1‐negative BC surface area ratio became significantly higher (4.1‐fold) than those of ZO‐1‐positive BCs. Based on these data, we calculated slopes of surface area changes, m, of each ZO‐1‐positive and ZO‐1‐negative BC. BCs with m ≤ 15 that fell within the 95% confidence interval of ZO‐1‐positive BCs were defined as ZO‐1‐positive. To validate this method, we compared the frequency of ZO‐1‐positive BCs, FZ, with that of BCs with m ≤ 15, FT, in culture using drugs that regulate TJ, or induce intrahepatic cholestasis. FT values were correlated with FZ under all culture conditions (R2 = .99). Our results indicate that the magnitude of BC surface area changes is a factor affecting TJ disruption, suggesting that maintaining TJ integrity by slowing BC dilation inhibits cell death.https://doi.org/10.1002/prp2.960bile canaliculusbile canaliculus dynamicsdrug‐induced intrahepatic cholestasisnon‐invasive evaluationtight junctionzonula occludens‐1 |
| spellingShingle | Rie Sonoi Yoshihisa Hagihara Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics Pharmacology Research & Perspectives bile canaliculus bile canaliculus dynamics drug‐induced intrahepatic cholestasis non‐invasive evaluation tight junction zonula occludens‐1 |
| title | Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| title_full | Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| title_fullStr | Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| title_full_unstemmed | Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| title_short | Quantitative understanding of HepaRG cells during drug‐induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| title_sort | quantitative understanding of heparg cells during drug induced intrahepatic cholestasis through changes in bile canaliculi dynamics |
| topic | bile canaliculus bile canaliculus dynamics drug‐induced intrahepatic cholestasis non‐invasive evaluation tight junction zonula occludens‐1 |
| url | https://doi.org/10.1002/prp2.960 |
| work_keys_str_mv | AT riesonoi quantitativeunderstandingofhepargcellsduringdruginducedintrahepaticcholestasisthroughchangesinbilecanaliculidynamics AT yoshihisahagihara quantitativeunderstandingofhepargcellsduringdruginducedintrahepaticcholestasisthroughchangesinbilecanaliculidynamics |