Ribose Cysteine Protects Against Acetaminophen-Induced Hepatic and Renal Toxicity

Abstract

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.

Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

“…Male mice (10-12 weeks old) were fasted overnight and then treated with APAP (500 mg/kg i.p.) or vehicle (phosphate-buffered saline) for 1, 2, or 18 h. Mice were fasted because unfed mice exhibit more consistent responses to APAP than do fed mice (Placke et al, 1987;Lucas et al, 2000). Mice were sacrificed at the indicated time points.…”

“…APAP and its metabolites in liver, blood, bile, and urine were analyzed using an HPLC method described by Chen et al (2003) and Lucas et al (2000) with minor modification. In brief, livers (0.1 g) were homogenized in 9 volumes of ice-cold methanol.…”

Comparison of S-Adenosyl-l-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

“…ity have been reported for clofibrate (Chen et al, 2002), ribose cysteine (Lucas et al, 2000;Lucas Slitt et al, 2005), L-cysteine glutathione-mixed disulfide (Berkeley et al, 2003), and 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (Srinivasan et al, 2001). The mechanism of APAP protection may be different between these agents and remains to be completely identified for clofibrate.…”

Standard of Care may not Protect against Acetaminophen‐Induced Nephrotoxicity

“…The fasted male CD-1 mouse model response to acetaminophen has been thoroughly characterized in our laboratories with reproducible hepatic and renal injury (Hart et al 1994;Lucas et al 2000). For intraperitoneal thiol rescue, N-acetyl-Lcysteine or Ribose-Cysteine (4 mmol/kg) in phosphate-buffered saline (pH 7.4) was given in three separate doses at 5, 60, and 120 min.…”