Ribose cysteine protects against acetaminophen-induced hepatic and renal toxicity

Ribose cysteine (RibCys) is a cysteine prodrug that increases both hepatic and renal glutathione with documented antagonism of acetaminophen (APAP)-in duced hepatotoxicity. To determine if RibCys could also protect against APA P-induced kidney damage, mice were injected with APAP (600 mg/kg) or APAP a nd 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 administra tion, and liver and kidney toxicity were assessed by plasma sorbitol dehydr ogenase (SDH) activity and blood urea nitrogen (BUN), respectively, and by histopathology. APAP treatment resulted in elevation of SDH activity and BU N 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 sever e hepatic centrilobular necrosis in 9/11 and renal proximal tubular necrosi s in 10/11 APAP-treated mice. However, no evidence of hepatic or renal toxi city was noted in any of the 12 APAP/RIB-treated mice. Utilizing the same t reatment regimen, APAP covalent binding to hepatic and renal cytosolic prot eins was assessed 4 hours after APAP challenge. RibCys cotreatment decrease d covalent binding to the 58-kDa acetaminophen-binding protein in both live r and kidney. RibCys decreased both toxicity and covalent binding after APA P administration, and in addition to protecting the liver, this cysteine pr odrug can also effectively protect the kidney from APAP-induced injury.