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Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.
- Source :
-
Gut microbes [Gut Microbes] 2024 Jan-Dec; Vol. 16 (1), pp. 2404138. Date of Electronic Publication: 2024 Sep 21. - Publication Year :
- 2024
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Abstract
- Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.
- Subjects :
- Animals
Female
Mice
Male
Oxidative Stress drug effects
Mice, Inbred C57BL
Hepatocytes drug effects
Hepatocytes metabolism
Liver drug effects
Liver metabolism
Glutathione metabolism
Acetaminophen toxicity
Gastrointestinal Microbiome drug effects
Chemical and Drug Induced Liver Injury drug therapy
Chemical and Drug Induced Liver Injury metabolism
Rotenone toxicity
Rotenone analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1949-0984
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gut microbes
- Publication Type :
- Academic Journal
- Accession number :
- 39305468
- Full Text :
- https://doi.org/10.1080/19490976.2024.2404138