Development of organoid-based drug metabolism model
| Autor: | Sukin Jeong, Enoch Park, Han Kyung Kim, Jongman Yoo, Soojung Hahn, JooHyun Jee |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cell Survival Antineoplastic Agents Biology urologic and male genital diseases Toxicology Dexamethasone Mice 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System beta-Naphthoflavone In vivo medicine Organoid Animals Humans Intestinal Mucosa Pharmacology Cytochrome P450 In vitro Mice Inbred C57BL Organoids Pancreatic Neoplasms 030104 developmental biology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Hepatocyte Toxicity Cancer research biology.protein Stem cell Drug metabolism |
| Zdroj: | Toxicology and Applied Pharmacology. 385:114790 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2019.114790 |
| Popis: | Cytochrome P450 (CYP) gene superfamily catalyzes oxidative metabolism of a wide variety of drugs, carcinogens, and endogenous biomolecules in the liver and intestinal organs. In vitro assay platforms such as primary hepatocyte and immortalized liver-derived cell lines have been developed to evaluate drug effects. However, several limitations have been suggested regarding discrepancies between in vitro and in vivo assays. In this study, we aimed to investigate drug metabolism and toxicity based on mouse small intestinal and liver organoids derived from resident stem cells. At first, expressions and activities of CYP subfamilies (CYPs) in intestinal and liver organoids were investigated. Organoids treated with three CYPs-inducers dexamethasone (Dex), β-naphthoflavone (BNF), and 1,4-bis-2-(3, 5-dichloropyridyloxy)-benzene (TCPOBOP) were evaluated for CYPs activities. The CYPs-induced intestinal and liver organoids were confirmed to digest more docetaxel, as colon cancer cell-line survived more in CYPs-induced organoid's medium than in non-induced organoid's medium. Then, the activity of docetaxel in a co-culture platform of mouse liver organoids and human pancreatic tumoroids was measured. We obtained significant statistical values on CYPs-induced metabolic activities: cell survival rates of pancreatic tumoroids co-cultured with docetaxel-treated undifferentiated, differentiated, and CYPs-induced differentiated organoids were 66.05 ± 2.14%, 89.20 ± 2.67%, and 101.90 ± 0.94%, respectively. To sum up, gene expression modification and drug metabolism evaluation were able to be done with organoids as done with tissues. In vivo-like in vitro investigation on drug toxicity may potentially be done with organoids as a stepping bridge to the clinical trial. |
| Databáze: | OpenAIRE |
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