| RRC ID |
58819
|
| 著者 |
Kawaguchi M, Nukaga T, Sekine S, Takemura A, Susukida T, Oeda S, Kodama A, Hirota M, Kouzuki H, Ito K.
|
| タイトル |
Mechanism-based integrated assay systems for the prediction of drug-induced liver injury.
|
| ジャーナル |
Toxicol Appl Pharmacol
|
| Abstract |
Drug-induced liver injury (DILI) can cause hepatic failure and result in drug withdrawal from the market. It has host-related and compound-dependent mechanisms. Preclinical prediction of DILI risk is very challenging and safety assessments based on animals inadequately forecast human DILI risk. In contrast, human-derived in vitro cell culture-based models could improve DILI risk prediction accuracy. Here, we developed and validated an innovative method to assess DILI risk associated with various compounds. Fifty-four marketed and withdrawn drugs classified as DILI risks of "most concern", "less concern", and "no concern" were tested using a combination of four assays addressing mitochondrial injury, intrahepatic lipid accumulation, inhibition of bile canalicular network formation, and bile acid accumulation. Using the inhibitory potencies of the drugs evaluated in these in vitro tests, an algorithm with the highest available DILI risk prediction power was built by artificial neural network (ANN) analysis. It had an overall forecasting accuracy of 73%. We excluded the intrahepatic lipid accumulation assay to avoid overfitting. The accuracy of the algorithm in terms of predicting DILI risks was 62% when it was constructed by ANN but only 49% when it was built by the point-added scoring method. The final algorithm based on three assays made no DILI risk prediction errors such as "most concern " instead of "no concern" and vice-versa. Our mechanistic approach may accurately predict DILI risks associated with numerous candidate drugs.
|
| 巻・号 |
394
|
| ページ |
114958
|
| 公開日 |
2020-5-1
|
| DOI |
10.1016/j.taap.2020.114958
|
| PII |
S0041-008X(20)30082-X
|
| PMID |
32198022
|
| MeSH |
Algorithms
Bile Acids and Salts / metabolism
Bile Canaliculi / pathology
Biological Assay / methods*
Cell Line
Chemical and Drug Induced Liver Injury / diagnosis*
Drug-Related Side Effects and Adverse Reactions / diagnosis*
Humans
Lipid Metabolism / drug effects
Maximum Tolerated Dose
Mitochondria / drug effects
Predictive Value of Tests*
Reproducibility of Results
|
| IF |
3.585
|
| 引用数 |
0
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2 |
