Curcumin pre-exposure in vivo prevents acetaminophen-induced apoptotic and necrotic cell deaths in the liver.

摘要

Curcumin (CUR; diferuloylmethane), a rhizome extract of Curcuma Longa L. is commonly used as a food coloring and flavoring agent. Although the oriental and ayurvedic medicines have traditionally used CUR in the treatment of numerous diseases, the conventional medicine has just begun to recognize its potential therapeutic value. Numerous experiments conducted by researchers around the globe have demonstrated CUR's ability to prevent and/or halt certain types of cancer, stop inflammation, and improve cardiovascular health. However, very few studies have examined its ability to protect against drug-induced organ injury. This study explored whether CUR pre-exposure has the potential to prevent acetaminophen (APAP)-induced: (i) organ injury in addition to (ii) apoptotic and necrotic cell deaths in the liver in-vivo. Additional goals were to determine whether these events were linked to APAP-induced oxidative stress, modulation of several pro- and antiapoptotic gene expressions and to the modes of cell death in the liver. In order to study CUR-APAP interaction, male B6C3F1 mice (CON, CUR, APAP, CUR+APAP) were orally gavaged with CUR (17 mg/kg, p.o.) for 12 days. On day 13, a single, high-dose of APAP (400 mg/kg, ip) was administered to groups 3 and 4, and all animals were sacrificed 24 hours later. Results indicated that APAP-induced liver injury associated events such as ALT (80 fold), lipid peroxidation (357%) and DNA fragmentation (469%) were considerably reduced to 3-fold, 134% and 162% respectively in CUR+APAP group. APAP-induced increase of pro-apoptotic gene (p53, Bax, caspase-3) and decrease of anti-apoptotic gene (Bcl-xL and Bcl-2) expressions were also alleviated by CUR pre-exposure, and these changes were mirrored in the pattern of apoptotic and necrotic cell deaths. In addition, enzymic and non-enzymic component investigations as well as histopathology findings clearly echoed the remarkable ability of curcumin to neutralize oxidative stress and protect the integrity of the genome, by acting as a powerful antioxidant during the notoriously hepatotoxic insult of APAP in the liver of B6C3F1 mice. It appears that CUR may impart a global organ protection against drug-induced organ toxicity by opposing events associated with both apoptosis and necrosis.;Key words: Hepatotoxicity, lipid peroxidation, oxidative stress, apoptosis, GSH, SOD, nitrate/nitrite content, Bax, Bcl-2, Bcl-xL, caspase-3, p53, Mdm2