| In vivo: |
| Environ Toxicol Pharmacol. 2012 Sep;34(2):608-17. | | Proteomic characterization of the possible molecular targets of pyrrolizidine alkaloid isoline-induced hepatotoxicity.[Pubmed: 22885678] |
Pyrrolizidine alkaloids (PAs) are distributed in plants worldwide including medicinal herbs or teas. In the present study, we investigated the effects of Isoline, which is a retronecine-type PA isolated from traditional Chinese medicinal herb Ligularia duciformis, on mouse liver proteins by using proteomic approaches.
METHODS AND RESULTS:
Firstly, our results showed that 110mg/kg Isoline increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum, and hepatic tissue pathological observation further confirmed Isoline-induced liver injury. Proteomic analysis showed that the liver samples from mice of Isoline group demonstrated about 13 differentially expressed proteins compared with normal group, and those proteins may be involved in Isoline-induced liver injury in mice. Next, all these 13 protein spots were identified by MALDI-TOF-TOF MS or LTQ MS; and among them 9 differentially expressed proteins are involved in the process of oxidative stress or cellular energy metabolism. Further lipid peroxidation analysis and ATPase assay confirmed the existing of oxidative injury induced by Isoline and consequent disruption of energy metabolism. Furthermore, an in silico drug target searching program INVDOCK identified 2 potential protein targets of Isoline, and the results are in support of proteomic analysis.
CONCLUSIONS:
In summary, the possible signaling molecules related with Isoline-induced liver injury were demonstrated in this study. | | Arch Toxicol. 2011 Oct;85(10):1267-79. | | The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity.[Pubmed: 21327617] | Cellular glutathione antioxidant system plays important roles in counteracting hepatotoxins-induced oxidative stress injury. The present study was designed to observe the differences of this system in newly weaned and young mice liver and its involvement in the susceptibility to Isoline-induced liver injury.
METHODS AND RESULTS:
Our results showed that liver reduced glutathione (GSH) amounts were higher in newly weaned mice than young mice. Glutamate-cysteine ligase (GCL) activity was higher in newly weaned mice due to the higher expression of catalytic subunit of GCL (GCLC) protein and mRNA. However, the activities of glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were higher in young mice liver, which might be due to the higher expression of GR, GPx-1, and GST-Pi proteins. Next, the results of AST analysis and histopathological evaluation showed that newly weaned mice demonstrated more severe liver injury induced by Isoline. Furthermore, liver GSH amounts and the activities of GR, GPx, and GST were all lower in newly weaned mice than young mice after treated with Isoline. Depletion of cellular GSH by D,L -buthionine-(S, R)-sulfoximine (BSO) aggravated Isoline-induced cytotoxicity, while N-acetyl-l cysteine (NAC) ameliorated such cytotoxicity. Furthermore, the inhibitors of GR, GPx, and GST all aggravated Isoline-induced cytotoxicity.
CONCLUSIONS:
In conclusion, our results demonstrated the differences of glutathione antioxidant system between newly weaned and young mice liver. Meanwhile, our results also revealed age-dependent liver injury induced by Isoline for the first time, which might be due to the different responses of glutathione antioxidant system to Isoline between newly weaned and young mice. |
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