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Ribose Cysteine Protects Against Acetaminophen-Induced Hepatic and Renal Toxicity

Department of Pharmaceutical Sciences, Toxicology Program, University of Connecticut, Storrs, Connecticut 06269-2092

Gayle Hennig

Department of Pathobiology, Toxicology Program, University of Connecticut, Storrs, Connecticut 06269-3089

Pamela K. Dominick

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112

Herbert E. Whiteley

Department of Pathobiology, Toxicology Program, University of Connecticut, Storrs, Connecticut 06269-3089

Jeanette C. Roberts

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112

Steven D. Cohen

Department of Pharmaceutical Sciences, Toxicology Program, University of Connecticut, Storrs, Connecticut 06269-2092

Ribose cysteine (RibCys) is a cysteine prodrug that increases both hepatic and renal glutathione with documented antagonism of acetaminophen (APAP)-induced hepatotoxicity. To determine if RibCys could also protect against APAP-induced kidney damage, mice were injected with APAP (600 mg/kg) or APAP and RibCys (1.0 g/kg) (APAP/RIB) followed by additional RibCys injections 1 and 2 hours later. Mice were euthanatized 10-12 hours after APAP administration, and liver and kidney toxicity were assessed by plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen (BUN), respectively, and by histopathology. APAP treatment resulted in elevation of SDH activity and BUN to 2,490 U/ml and 47 mg/dl, respectively. By contrast, SDH and BUN values for APAP/RIB-treated mice were not different from controls, 0 U/ml and 31 mg/dl, respectively. Histopathologic examination revealed moderate to severe hepatic centrilobular necrosis in 9/11 and renal proximal tubular necrosis in 10/11 APAP-treated mice. However, no evidence of hepatic or renal toxicity was noted in any of the 12 APAP/RIB-treated mice. Utilizing the same treatment regimen, APAP covalent binding to hepatic and renal cytosolic proteins was assessed 4 hours after APAP challenge. RibCys cotreatment decreased covalent binding to the 58-kDa acetaminophen-binding protein in both liver and kidney. RibCys decreased both toxicity and covalent binding after APAP administration, and in addition to protecting the liver, this cysteine prodrug can also effectively protect the kidney from APAP-induced injury.

Key Words: Paracetamol • 4-hydroxy-acetanilide • RibCys • 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid • liver • kidney • antidote

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