Effect of WF11605, a novel LTB4 antagonist on galactosamine-induced hepatitis in rats.

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The pathogenic mechanism of fulminant hepatitis induced by a 400 mg/kg D-galactosamine was investigated in male Wistar rats. The extent of liver injury was assessed by measurements of serum transaminases, serum total bilirubin and relative liver weight at 24 hr after D-galactosamine administration. WF 11605 is a selective antagonist of leukotriene B4 (LTB4) . The compound was isolated as a product of fungal metabolite. WF 11605 inhibited LTB4-induced chemotaxis of rabbit polymorphonuclear leukocyte (PMN) with an IC50 value of 1.7 × 10-7 M and blocked 3H-LTB4 binding to PMN membrane at 5.6 × 10-6 M (IC50) . WF 11605 also inhibited LTB4-induced degranulation of rabbit PMN at 3.0 × 10-6 M (IC50) . However, the compound did not show any inhibitory effect on platelet activating factor (PAF) -and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) -induced degranulation at concentrations up to 10-4 M. In order to determine whether LTB4 contributes to the occurrence of the hepatitis in rats, we therefore attempted to prevent the hepatitis by WF 11605. Intraperitoneally administered WF 11605 at doses of 10, 32 and 100 mg/kg significantly prevented the increase of serum transaminases and bilirubin in a dose dependent manner. We conclude from our results that LTB4 might be involved in the pathogenesis of D-galactosamine-induced hepatitis in rats.
日本炎症・再生医学会の論文