PMID- 23161217 OWN - NLM STAT- MEDLINE DCOM- 20130328 LR - 20211021 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 344 IP - 2 DP - 2013 Feb TI - Suramin decreases injury and improves regeneration of ethanol-induced steatotic partial liver grafts. PG - 417-25 LID - 10.1124/jpet.112.199919 [doi] AB - 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 approximately 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 approximately 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-alpha (TNF-alpha) 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-alpha and caspase activation in FPG. Transforming growth factor-beta (TGF-beta), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-beta formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-alpha and TGF-beta formation. FAU - He, Songqing AU - He S AD - Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, PO Box 250140, Charleston, SC 29425, USA. FAU - Rehman, Hasibur AU - Rehman H FAU - Shi, Yanjun AU - Shi Y FAU - Krishnasamy, Yasodha AU - Krishnasamy Y FAU - Lemasters, John J AU - Lemasters JJ FAU - Schnellmann, Rick G AU - Schnellmann RG FAU - Zhong, Zhi AU - Zhong Z LA - eng GR - DK37034/DK/NIDDK NIH HHS/United States GR - R01 AA017756/AA/NIAAA NIH HHS/United States GR - R56 DK037034/DK/NIDDK NIH HHS/United States GR - C06 RR015455/RR/NCRR NIH HHS/United States GR - DK70844/DK/NIDDK NIH HHS/United States GR - R37 DK037034/DK/NIDDK NIH HHS/United States GR - R01 DK037034/DK/NIDDK NIH HHS/United States GR - R01 DK073336/DK/NIDDK NIH HHS/United States GR - AA017756/AA/NIAAA NIH HHS/United States GR - R01 DK070844/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20121116 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 3K9958V90M (Ethanol) RN - 6032D45BEM (Suramin) SB - IM MH - Animals MH - Ethanol/*pharmacology MH - Fatty Liver, Alcoholic/drug therapy/pathology/*surgery MH - Female MH - Graft Survival/*drug effects MH - Liver/*drug effects/pathology/surgery MH - Liver Function Tests MH - Liver Regeneration/*drug effects MH - *Liver Transplantation/methods MH - Organ Size MH - Rats MH - Rats, Inbred Lew MH - Suramin/administration & dosage/*therapeutic use PMC - PMC3558824 EDAT- 2012/11/20 06:00 MHDA- 2013/03/30 06:00 PMCR- 2014/02/01 CRDT- 2012/11/20 06:00 PHST- 2012/11/20 06:00 [entrez] PHST- 2012/11/20 06:00 [pubmed] PHST- 2013/03/30 06:00 [medline] PHST- 2014/02/01 00:00 [pmc-release] AID - jpet.112.199919 [pii] AID - JPET_199919 [pii] AID - 10.1124/jpet.112.199919 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2013 Feb;344(2):417-25. doi: 10.1124/jpet.112.199919. Epub 2012 Nov 16.