Liver Injury Caused by Green Tea Extract in PD-1–/– Mice: An Impaired Immune Tolerance Model for Idiosyncratic Drug-Induced Liver Injury
| Autor: | Yanshan Cao, Tiffany Cho, Karen Yeung, Jack Uetrecht, Xijin Wang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Idiosyncratic drug reaction
Green tea extract 010501 environmental sciences Pharmacology Toxicology 01 natural sciences Immune tolerance 03 medical and health sciences chemistry.chemical_compound Immune system medicine 030304 developmental biology 0105 earth and related environmental sciences Liver injury 0303 health sciences biology business.industry Catechin General Medicine medicine.disease 3. Good health chemistry Alanine transaminase biology.protein business CD8 |
| Zdroj: | Chemical Research in Toxicology. 34:849-856 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.0c00485 |
| Popis: | Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1-/- mouse model in combination with anti-CTLA-4 to block immune checkpoints and impair immune tolerance. Treatment of these mice with drugs that cause IDILI in humans led to delayed-onset liver injury with characteristics similar to IDILI in humans. The current study investigates the effects of green tea extract, a weight-loss dietary supplement that has been reported to cause IDILI in humans. Green tea extracts contain a highly variable content of catechins including (-)-epigallocatechin gallate, the major catechin in green tea formulations. If the liver injury caused by green tea extract in humans is immune-mediated, it may occur in our impaired immune tolerance model. Female PD-1-/- mice treated with anti-CTLA-4 antibody and green tea extract (500 mg/kg), a dose that is considered a no-observed-adverse-effect level for liver in rodents, produced a delayed onset increase in serum alanine transaminase levels and an increase in hepatic CD8+ T cells. In contrast, the response in male PD-1-/- mice was less pronounced, and there was no evidence of liver injury in wild-type mice. These findings are consistent with the hypothesis that the IDILI caused by green tea extract is immune-mediated and is similar to IDILI caused by medications that are associated with IDILI. |
| Databáze: | OpenAIRE |
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