Abstract
Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is used to treat hypertension, postpartum hemorrhage, dysentery, and amenorrhea as a traditional medicine in Asia. We investigated the effect of rutaecarpine on acetaminophen-induced hepatotoxicity in mice. Rutaecarpine was administered orally daily for seven consecutive days, followed by intraperitoneal injection of acetaminophen in mice on day seven to induce hepatotoxicity. Rutaecarpine pretreatment significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activities and hepatic malondialdehyde content and prevented acetaminophen-induced hepatic glutathione depletion. Furthermore, CYP2E1 expression was decreased by rutaecarpine pretreatment in a dose-dependent manner. Rutaecarpine pretreatment inhibited acetaminophen-induced expression of inflammatory cytokines by inhibiting NF-κB activation by JNK1/2. Also, rutaecarpine pretreatment promoted Nrf2-mediated activation of the antioxidant enzymes GCLC, HO-1, and NQO1. This indicates that the protective effect of rutaecarpine during acetaminophen-induced acute liver injury is mediated by the activation of antioxidant enzymes. Therefore, rutaecarpine has a protective effect of APAP-induced liver damage.
Highlights
The liver is responsible for metabolism and detoxifying drugs
We have reported that Rut protects against t-BHP-induced hepatotoxicity by upregulating antioxidant enzymes via the CaMKII-Akt and Nrf2/antioxidant responsive element (ARE) pathways [12]
The findings show that Rut prevented APAP-induced acute liver injury by activating antioxidant enzymes
Summary
The liver is responsible for metabolism and detoxifying drugs. Drug-induced liver injury and liver failure lead to a high morbidity and mortality rate worldwide [1]. Most druginduced hepatotoxicity occurs from accidental or intentional overdose of acetaminophen (APAP). APAP accounts for approximately 50% of all cases of liver injury in the United. APAP is safe at therapeutic doses and can be purchased without a prescription in combination with other drugs, but an overdose of APAP can cause serious liver damage in animals and humans [3]. APAP overdose results in approximately 80,000 emergency room visits and 30,000 hospitalizations annually in the United States [4,5]
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