Dose- and time-dependent effects of luteolin on heat shock protein gp96 expression in carbon tetrachloride-induced hepatotoxicity in mice

Objectives. The hepatoprotective effect of luteolin was poorly studied. Literature overview shows that most of the studies on luteolin actions have been performed in vitro. Carbon tetrachloride (CCl4) is a well-known model compound for producing chemical hepatic injury. This study investigated the protective effects of the flavonoid luteolin on the CCl4-induced hepatotoxicity in mice. Methods. Luteolin dissolved in DMSO was administered intraperitoneally (i.p.) at 5 or 50 mg/kg as a single dose, and once daily for 2 consecutive days, respectively. Two hours after the final treatment, the mice were treated with CCl4 (20 mg/kg, i.p.). The mice were killed 24 hours after administrating CCl4. Results. CCl4-induced hepatotoxicity was reduced in a dose- and time-dependent manner, as determined by decreased serum aminotransferase activities and liver histopathology. CCl4 administration caused extensive centrilobular necrosis with loss of hepatocyte structure, vacuolar fatty change and marked inflammatory cell infiltration. Luteolin pretreatment greatly reduced necrosis, inflammatory infiltration and fatty changes. CCl4 intoxication resulted in an overexpression of heat shock protein gp96 in the mice liver, which was almost completely attenuated by the luteolin pretreatment. Conclusions. The data suggest that the overexpression of gp96 in liver tissue is an early molecular response in acute, chemically induced liver damage in mice, which correlates with the degree of tissue damage. The hepatoprotective effect of luteolin against CCl4 hepatotoxicity was higher in animals pretreated with luteolin for 2 consecutive days. This suggests that the protection might be due to induction of some adaptive mechanisms. The data indicate that luteolin could be effective in protecting mice from the hepatotoxicity produced by CCl4.