Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors

Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors

^*Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan; ^†Research and Development Center, Terumo Corporation, Kanagawa 259-0151, Japan; ^‡Division of Molecular Pathology, Graduate School of Medical Sciences, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan; and ^§Department of Pediatrics and Clinical Chemistry, Free University Hospital, Amsterdam, The Netherlands

Edited by William S. Sly, Saint Louis University School of Medicine, St. Louis, MO, and approved June 1, 1998 (received for review March 4, 1998)

Abstract

Tyrosinemia type 1, caused by mutations in the fumarylacetoacetate hydrolase gene (Fah), is characterized by severe liver injury. We earlier developed a tyrosinemic mouse model with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd) deficiencies. Apoptosis of hepatocytes was induced and an acute onset of liver failure occurred after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH. Cytochrome c was released from mitochondria prior to liver failure in the Fah ^−/− Hpd−/− double-mutant mice after the administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced the release of cytochrome c from the mitochondria. We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: Department of Pediatrics, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. e-mail: endo{at}kaiju.medic.kumamoto-u.ac.jp.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

HT1,

hereditary tyrosinemia type 1;

HPD,

4-hydroxyphenylpyruvate dioxygenase;

HGA,

homogentisic acid;

FAA,

fumarylacetoacetate;

FAH,

fumarylacetoacetate hydrolase;

moi,

multiplicity of infection;

YVAD,

Ac-Tyr-Val-Ala-Asp-CHO;

DEVD,

Ac-Asp-Glu-Val-Asp-CHO