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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Suramin Decreases Injury and Improves Regeneration of Ethanol-Induced Steatotic Partial Liver Grafts

Songqing He, Hasibur Rehman, Yanjun Shi, Yasodha Krishnasamy, John J. Lemasters, Rick G. Schnellmann and Zhi Zhong
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 417-425; DOI: https://doi.org/10.1124/jpet.112.199919
Songqing He
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Hasibur Rehman
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Yanjun Shi
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Yasodha Krishnasamy
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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John J. Lemasters
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Rick G. Schnellmann
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Zhi Zhong
Departments of Drug Discovery and Biomedical Sciences (S.H., H.R., Y.S., Y.K., J.J.L., R.G.S., Z.Z.) and Biochemistry and Molecular Biology (J.J.L., R.G.S.), and Hollings Cancer Center (J.J.L., R.G.S., Z.Z.), Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson, Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.); and Laboratory of Liver Injury and Repair Molecular Medicine, the Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China (S.H.)
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Abstract

Steatotic grafts are excluded for use in partial liver transplantation (LT) because of the increased risk of primary nonfunction. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, intragastric administration), reduced in size to ∼1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin levels as well as hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/kg, i.p.) decreased ALT by ∼60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-2′-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 hours, and the mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and the mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. Tumor necrosis factor-α (TNF-α) mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and caspase-3 in FPG. Suramin decreased TNF-α and caspase activation in FPG. Transforming growth factor-β (TGF-β), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-β formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-α and TGF-β formation.

Footnotes

  • This research was supported in part by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK70844 and DK37034]; and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA017756]. Animals were housed in the animal facility of the Medical University of South Carolina and supported in part by the National Institutes of Health [Grant C06 RR015455].

  • dx.doi.org/10.1124/jpet.112.199919.

  • Received September 10, 2012.
  • Accepted November 15, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Suramin and Transplantation of Fatty Partial Liver Grafts

Songqing He, Hasibur Rehman, Yanjun Shi, Yasodha Krishnasamy, John J. Lemasters, Rick G. Schnellmann and Zhi Zhong
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 417-425; DOI: https://doi.org/10.1124/jpet.112.199919

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Suramin and Transplantation of Fatty Partial Liver Grafts

Songqing He, Hasibur Rehman, Yanjun Shi, Yasodha Krishnasamy, John J. Lemasters, Rick G. Schnellmann and Zhi Zhong
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 417-425; DOI: https://doi.org/10.1124/jpet.112.199919
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