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The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

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. 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. 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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Abbreviations

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

GCL:

Glutamate-cysteine ligase

GR:

Glutathione reductase

GPx:

Glutathione peroxidase

GST:

Glutathione-S-transferase

NAC:

N-acetyl-l cysteine

ROS:

Reactive oxygen species

DILI:

Drug-induced liver injury

LPS:

Lipopolysaccharide

PAs:

Pyrrolizidine alkaloids

DTNB:

5, 5′-Dithio-bis (2-nitrobenzoic acid)

BCNU:

1,3-Bis(2-chloroethyl)-1-nitrourea

BSO:

d,l-buthionine-(S, R)-sulfoximine

MA:

Mercaptosuccinic acid

EA:

Ethacrynic acid

CDNB:

1-Chloro-2, 4-dinitrophenol

RT-PCR:

Reverse transcription-polymerase chain reaction

MTT:

3-(4, 5-Dimethyl-thiazol-2-yl) 2, 5-diphenyltetra-zolium bromide

AST:

Aspartate aminotransferase

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Acknowledgments

This work was financially supported by National Natural Science Foundation of China (30801544), National Basic Research Program Foundation of China (2006CB504704), Innovation Program of Shanghai Municipal Education Commission (09ZZ125), and Shanghai Rising-Star Program (10QH1402200).

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Authors and Affiliations

  1. The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, 201210, Shanghai, China

    Qing-Ning Liang, Ping Jiang, Li-Li Ji & Zheng-Tao Wang

  2. Shanghai R&D Centre for Standardization of Chinese Medicines, 201210, Shanghai, China

    Li-Li Ji & Zheng-Tao Wang

  3. Department of Medicine, The University of Hong Kong, Hong Kong, China

    Qing-Ning Liang

  4. Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, 200437, Shanghai, China

    Yu-Chen Sheng, Yu-Ye Xia & Yang Min

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  1. Qing-Ning Liang
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Correspondence to Li-Li Ji or Zheng-Tao Wang.

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Liang, QN., Sheng, YC., Jiang, P. et al. The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity. Arch Toxicol 85, 1267–1279 (2011). https://doi.org/10.1007/s00204-011-0664-7

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  • DOI: https://doi.org/10.1007/s00204-011-0664-7

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