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

Abstract

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 (3mg/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.

• Authors: Kazumoto Murata, Minoru Hamada, Kazushi Sugimoto, Takeshi Nakano
• Journal: Journal of hepatology (J Hepatol) Vol. 46 Issue 2 Pg. 322-9 (Feb 2007) ISSN: 0168-8278 [Print] Netherlands
• PMID: 17156885 (Publication Type: Journal Article)

Chemical References

• Histones
• fas Receptor
• Hydralazine
• Acetyltransferases
• Arylamine N-Acetyltransferase
• NAT2 protein, human
• Todralazine

Topics

• Acetylation (drug effects)
• Acetyltransferases (analysis)
• Animals
• Arylamine N-Acetyltransferase (genetics)
• Disease Models, Animal
• Female
• Histones (antagonists & inhibitors, metabolism)
• Humans
• Hydralazine (analogs & derivatives)
• Liver (drug effects, metabolism, pathology)
• Liver Failure (chemically induced, metabolism, pathology)
• Liver Regeneration (drug effects)
• Mice
• Todralazine (toxicity)
• fas Receptor (antagonists & inhibitors)