Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans
Abstract
:1. Introduction
2. Results
2.1. Preparation of Se/GSH-Depleted Rats
2.2. Profiling of Se/GSH-Depleted Rats
2.3. Toxicity Study of Flutamide Using Se/GSH-Depleted Rats
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Animals
4.3. Preparing Se/GSH-Depleted Rats
4.4. Toxicity Study of Flutamide Using Se/GSH-Depleted Rats
4.5. Sampling of Blood and Liver Samples
4.6. Measurements of Serum Se Levels
4.7. Measurements of Hepatic GSH and GSSG Levels
4.8. Measurements of Hepatic MDA Levels
4.9. Western Blotting
4.10. Measurements of Plasma Liver Function Parameters Levels
4.11. Histopathology
4.12. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Parameters | Group | Week 2 | Week 4 | Week 5 |
---|---|---|---|---|
Serum Se level (μg/L) | Control | 509.0 ± 34.8 | 550.0 ± 34.8 | 607.0 ± 69.7 |
Se/GSH (−) | 355.0 ± 4.6 ** | 396.0 ± 56.0 * | 412.0 ± 79.7 * | |
Hepatic GSH level (μmol/g liver) | Control | 2.90 ± 0.10 | 3.03 ± 0.06 | 3.53 ± 0.35 |
Se/GSH (−) | 5.37 ± 0.97 * | 5.80 ± 0.89 ** | 1.43 ± 0.47 ** | |
Hepatic GSSG level (μmol/g liver) | Control | 0.95 ± 0.15 | 1.44 ± 0.56 | 1.47 ± 0.22 |
Se/GSH (−) | 0.16 ± 0.04 ** | 0.11 ± 0.03 * | 0.61 ± 0.33 * | |
GSSG/GSH ratio | Control | 0.33 ± 0.01 | 0.47 ± 0.17 | 0.41 ± 0.17 |
Se/GSH (−) | 0.03 ± 0.01 ** | 0.02 ± 0.002 * | 0.41 ± 0.10 | |
Hepatic MDA level (×10−2 μmol/g liver) | Control | 13.7 ± 0.3 | 12.6 ± 0.4 | 12.2 ± 0.5 |
Se/GSH (−) | 13.4 ± 0.1 | 14.4 ± 0.4 ** | 14.3 ± 0.4 ** | |
Plasma AST level (U/L) | Control | 75.7 ± 1.5 | 57.3 ± 6.5 | 59.0 ± 7.5 |
Se/GSH (−) | 65.7 ± 8.6 | 60.0 ± 57.3 | 55.7 ± 1.5 | |
Plasma ALT level (U/L) | Control | 25.7 ± 4.0 | 18.3 ± 2.5 | 22.3 ± 7.4 |
Se/GSH (−) | 21.0 ± 3.0 | 21.0 ± 1.7 | 17.3 ± 3.2 | |
Plasma T-BIL level (mg/dL) | Control | 0.047 ± 0.006 | 0.053 ± 0.021 | 0.053 ± 0.025 |
Se/GSH (−) | 0.043 ± 0.006 | 0.050 ± 0.010 | 0.053 ± 0.021 | |
Plasma GLDH level (U/L) | Control | 18.3 ± 1.2 | 16.7 ± 2.3 | 15.7 ± 2.9 |
Se/GSH (−) | 14.7 ± 2.9 | 17.0 ± 4.4 | 15.0 ± 2.6 | |
Plasma SDH level (U/L) | Control | 1.17 ± 0.76 | 2.17 ± 1.44 | 4.33 ± 1.53 |
Se/GSH (−) | 1.67 ± 1.15 | 2.17 ± 2.47 | 4.00 ± 2.00 |
Dose Level of Flutamide (mg/kg/day) | Se/GSH (+) | Se/GSH (−) | ||
---|---|---|---|---|
0 | 150 | 0 | 150 | |
Hypertrophy, hepatocyte, centrilobular | −: 5 | ±: 3 | −: 5 | ±: 2 |
+: 2 | +: 3 | |||
Infiltration, inflammatory cell, periportal | −: 5 | −: 5 | −: 5 | −: 4 |
±: 1 | ||||
Single cell necrosis, hepatocyte, centrilobular | −: 5 | −: 5 | −: 5 | −: 4 |
±: 1 | ||||
Necrosis, hepatocyte, focal, subcapsular | −: 5 | −: 5 | −: 5 | −: 5 |
+: 1 |
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Goda, K.; Muta, K.; Yasui, Y.; Oshida, S.-i.; Kitatani, K.; Takekoshi, S. Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans. Int. J. Mol. Sci. 2019, 20, 3141. https://doi.org/10.3390/ijms20133141
Goda K, Muta K, Yasui Y, Oshida S-i, Kitatani K, Takekoshi S. Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans. International Journal of Molecular Sciences. 2019; 20(13):3141. https://doi.org/10.3390/ijms20133141
Chicago/Turabian StyleGoda, Keisuke, Kyotaka Muta, Yuzo Yasui, Shin-ichi Oshida, Kanae Kitatani, and Susumu Takekoshi. 2019. "Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans" International Journal of Molecular Sciences 20, no. 13: 3141. https://doi.org/10.3390/ijms20133141