Acetaminophen is a commonly used drug for mild to moderate pain relief; however, acetaminophen toxicity due to the formation of toxic metabolites is a major cause of drug-induced liver injury. Methylene blue is an FDA-approved drug for the treatment of methemoglobinemia and has potential applications in the treatment of carbon monoxide and cyanide poisoning. Leuco-methylene blue, a colorless form of methylene blue, is more effective in entering cells and counteracting oxidative stress, making it a valuable option in regulating mitochondrial function and ATP production. In this study, we aimed to evaluate the effect of LMB on liver damage caused by acetaminophen toxicity. Thirty-six rats were divided into six groups: control, APAP, NAC, LMB, MB, and NAC+LMB. All groups except the control received acetaminophen (1500 mg/kg), followed by treatments with NAC (100 mg/kg), LMB (5 mg/kg), MB (5 mg/kg), and NAC+LMB after 3 hours. The rats were sacrificed 24 hours post-acetaminophen administration. LMB significantly reduced serum levels of liver enzymes (ALT, AST, and ALP) and increased the expression of genes involved in mitochondrial biogenesis and antioxidant defense (PGC-1, Nrf2, and Tfam). Additionally, LMB significantly increased total antioxidant capacity and glutathione reductase levels, decreased the prooxidant-antioxidant balance (PAB), and reduced the expression of inflammatory cytokines (IL-6 and TNF-α) in the liver tissue. LMB effectively reduced the severity of acetaminophen-induced liver damage through antioxidant and anti-inflammatory effects. LMB can effectively ameliorate APAP-induced toxicity in rats, with comparable efficacy to N-acetylcysteine with respect to most complications of acetaminophen-induced toxicity in rats.

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