Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice.
Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.
1 Department of Bioindustry Technology, Da-Yeh University , Taiwan, Republic of China .
Ming-Shiun
MS
Tsai
2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .
Chia-Chih
CC
Chien
2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .
Ting-Hui
TH
Lin
2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .
Chia-Chi
CC
Liu
3 Department of Nutrition, Chung Shan Medical University , Taiwan, Republic of China .
Rosa Huang
RH
Liu
4 Department of Life Sciences, National Chung Hsing University , Taiwan, Republic of China .
Hong-Lin
HL
Su
5 Laboratory of Comparative Pathology, Department of Education and Research, Taichung Veterans General Hospital , Taiwan, Republic of China .
Yung-Tsung
YT
Chiu
2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .|6 Department of Medical Research, Chung Shan Medical University Hospital , Taiwan, Republic of China .
Sue-Hong
SH
Wang
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives; D000111:Acetylcysteine / Q000627:therapeutic use; D000410:Alanine Transaminase / Q000097:blood; D032429:Alpinia / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D036562:Helichrysum / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D012838:Silymarin / Q000627:therapeutic use
D000975:Antioxidants; D005419:Flavonoids; D010936:Plant Extracts; D020011:Protective Agents; D012838:Silymarin; C037032:galangin; D000082:Acetaminophen; C063776:propacetamol; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase; D005978:Glutathione; D000111:Acetylcysteine
galangin; liver and kidney protections; n-acetylcysteine; novel drug overdose mouse models; propacetamol-induced acute liver injury; propacetamol-induced kidney injury