e-3330 and Chemical-and-Drug-Induced-Liver-Injury

The effect of E3330 ((2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-++ +propenoic acid), a novel quinone derivative, was studied in the galactosamine-induced hepatitis model in F344 rats, in which endogenous endotoxin is believed to play a critical pathogenetic role. Subcutaneous injection of 300 mg/kg of galactosamine into rats resulted in liver injury. Oral treatment with E3330 (10-100 mg/kg) 1 hr after galactosamine challenge attenuated the liver injury. E3330 was also effective when administered p.o. 6 or 12 hr after galactosamine challenge. Subcutaneous injection of 1000 mg/kg of galactosamine into rats resulted in more severe liver injury with endotoxemia. The plasma endotoxin was detected 24 to 48 hr after the galactosamine challenge. The time course of increase in plasma endotoxin level was in good agreement with that in plasma aminotransferase activity. E3330 (100 mg/kg) significantly attenuated the liver injury, but did not affect the endotoxin level. Exogenous administration of endotoxin enhanced the hepatotoxicity of galactosamine. Pretreatment with E3330 also protected rats from severe liver injury induced with endotoxin plus galactosamine. These results suggest that E3330 may exert its hepatoprotective effects through inhibition of an effect of endotoxin in galactosamine-induced hepatitis in rats.

Topics: Animals; Benzoquinones; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Endotoxins; Galactosamine; Lipopolysaccharides; Male; Propionates; Rats; Rats, Inbred F344

Oral pretreatment with E3330, a novel quinone derivative, attenuated liver injury induced with tumor necrosis factor-alpha in galactosamine-sensitized mice. Tumor necrosis factor-alpha is known to induce inflammatory mediators such as leukotrienes and prostanoids. An in vitro study showed that E3330 inhibited the generation of leukotriene B4 and thromboxane B2, but enhanced prostaglandin E2 generation from rat peritoneal exudate cells stimulated with the Ca(2+)-ionophore, A23187. These findings suggest that the protective effect of E3330 on galactosamine/tumor necrosis factor-alpha hepatitis is due at least in part to its inhibition of the generation of leukotrienes. The inhibition of thromboxane B2 generation or the enhancement of prostaglandin E2 generation by E3330 may also contribute to its hepatoprotective effect.

Topics: Animals; Ascitic Fluid; Benzoquinones; Chemical and Drug Induced Liver Injury; Dinoprostone; Galactosamine; In Vitro Techniques; Leukotriene B4; Male; Mice; Mice, Inbred C3H; Propionates; Rats; Thromboxane B2; Tumor Necrosis Factor-alpha