A novel mechanism for drug-induced liver failure: inhibition of histone acetylation by hydralazine derivatives.
OBJECTIVE
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.
Murata
Kazumoto
K
First Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. atarum@clin.medic.mie-u.ac.jp
Hamada
Minoru
M
Sugimoto
Kazushi
K
Nakano
Takeshi
T
D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000032:analysis; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000031:analogs & derivatives*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D014032:Todralazine / Q000633:toxicity*; D019014:fas Receptor / Q000037:antagonists & inhibitors
D006657:Histones; D019014:fas Receptor; D006830:Hydralazine; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D014032:Todralazine