Reference - Detail
| RRC ID | 68436 |
|---|---|
| Author | Negoro R, Yamada N, Watanabe K, Kono Y, Fujita T. |
| Title | Generation of Caco-2 cells stably expressing CYP3A4·POR·UGT1A1 and CYP3A4·POR·UGT1A1*6 using a PITCh system. |
| Journal | Arch Toxicol |
| Abstract |
The small intestine plays a critical role in the absorption and metabolism of orally administered drugs. Therefore, a model capable of evaluating drug absorption and metabolism in the small intestine would be useful for drug discovery. Patients with genotype UGT1A1*6 (exon 1, 211G > A) treated with the antineoplastic drug SN-38 have been reported to exhibit decreased glucuronide conjugation and increased incidence of intestinal toxicity and its severe side effects, including severe diarrhea. To ensure the safety of drugs, we must develop a drug metabolism and toxicity evaluation model which considers UGT1A1*6. In this study, we generated CYP3A4·POR·UGT1A1 KI- and CYP3A4·POR·UGT1A1*6 KI-Caco-2 cells for pharmaceutical research using a PITCh system. The CYP3A4·POR·UGT1A1 KI-Caco-2 cells were shown to express functional CYP3A4 and UGT1A1. The CYP3A4·POR·UGT1A1*6 KI-Caco-2 cells were sensitive to SN-38-induced intestinal toxicity. We thus succeeded in generating CYP3A4·POR·UGT1A1 KI- and CYP3A4·POR·UGT1A1*6 KI-Caco-2 cells, which can be used in pharmaceutical research. We also developed an intestinal epithelial cell model of patients with UGT1A1*6 and showed that it was useful as a tool for drug discovery. |
| Volume | 96(2) |
| Pages | 499-510 |
| Published | 2022-2-1 |
| DOI | 10.1007/s00204-021-03175-0 |
| PII | 10.1007/s00204-021-03175-0 |
| PMID | 34654938 |
| MeSH | Antineoplastic Agents / toxicity Caco-2 Cells / enzymology Cytochrome P-450 CYP3A / genetics* Drug Discovery / methods Genotype Glucuronosyltransferase / genetics* Humans Intestinal Mucosa / cytology Intestinal Mucosa / drug effects Intestinal Mucosa / enzymology* Intestine, Small / cytology Intestine, Small / drug effects Intestine, Small / enzymology* Irinotecan / toxicity |
| IF | 5.059 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | CACO-2(RCB0988) |