Protective effects of (2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4- benzoquinoyl)]-2-nonyl-2-propenoic acid on endotoxin-mediated hepatitis in mice.
E3330 [(2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2- propenoic acid] is a newly synthesized hepatoprotective quinone derivative. We examined the protective effects and possible mechanism of action of E3330 in three different endotoxin (lipopolysaccharide)-induced murine hepatitis models, in which tumor necrosis factor is suggested to play a critical role in the pathogenesis. One of these models was induced by i.v. injection of lipopolysaccharide in combination with D-galactosamine to mice. Oral pretreatment with E3330 improved the survival rate and attenuated the increase in plasma aminotransferase activities of the survivors. The other two models were induced by i.v. injection of lipopolysaccharide or a mixture of D-galactosamine and lipopolysaccharide in Propionibacterium acnes-primed mice. In both of these models, tumor necrosis factor was detected in the plasma within 3 hr of the injection. Oral pretreatment with E3330 attenuated the elevation of plasma tumor necrosis factor activity and protected mice from liver injury. Furthermore, E3330 inhibited the production of tumor necrosis factor from cultured Propionibacterium acnes-elicited murine peritoneal macrophages on stimulation with lipopolysaccharide in vitro. These findings suggest that the inhibition by E3330 of tumor necrosis factor production is the major mechanism of the protective effect of E3330 in these endotoxin-mediated hepatitis models in mice.
Nagakawa
J
J
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Hishinuma
I
I
Miyamoto
K
K
Hirota
K
K
Abe
S
S
Yamanaka
T
T
Katayama
K
K
Yamatsu
I
I
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D016227:Benzoquinones / Q000008:administration & dosage / Q000627:therapeutic use*; D004731:Endotoxins / Q000633:toxicity*; D005688:Galactosamine / Q000633:toxicity*; D006520:Hepatitis, Animal / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011422:Propionates / Q000008:administration & dosage / Q000627:therapeutic use*; D011425:Propionibacterium acnes; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016227:Benzoquinones; D004731:Endotoxins; D008070:Lipopolysaccharides; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha; C075569:E 3330; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase