A novel mechanism for drug-induced liver failure: Inhibition of histone acetylation by hydralazine derivatives

作者：Murata Kazumoto^*; Hamada Minoru; Sugimoto Kazushi; Nakano Takeshi

来源：Journal of Hepatology, 2007, 46(2): 322-329.

DOI：10.1016/j.jhep.2006.09.017

• liver regeneration failure
• todralazine
• histone acetyltransferase
• n-acetyltransferase
• immunohistochemistry

Background/Aims: The aim of this study was to investigate the precise mechanism of liver failure by hydralazine derivatives, with special reference to liver regeneration failure.
Methods: Histone acetylation and proliferation of hepatocytes were evaluated by immunohistochemistry with anti-acetylated histone H4 and proliferating cell nuclear antigen (PCNA). Inhibition of histone acetylation by drugs was determined by in vitro histone acetylation assay. Mice livers fed with todralazine for 1 or 4 months were subjected to immunohistochemistry and Western blotting. Todralazine-fed mice were challenged with anti-Fas to check liver regeneration failure.
Results: On immunohistochemistry, histone acetylation in the hepatocytes was significantly impaired in patients with hydralazine derivatives. In an in vitro acetyl transferase assay, histone acetylation was inhibited by hydralazine derivatives in a dose-dependent manner. Mice fed with todralazine (3 mg/day) for 4 months showed impairment of histone acetylation in hepatocytes whereas no inhibition was observed in mice fed with todralazine for 1 month. Anti-Fas challenge to todralazine-fed mice resulted in impairment of liver regeneration in respect of liver weight loss with impairment of histone acetylation in hepatocytes.
Conclusions: Todralazine could inhibit catalysis of histone acetyltransferase and long-term administration of todralazine may impair histone acetylation of the hepatocytes, resulting in liver regeneration failure.

• 出版日期2007-2