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J. Biol. Chem., Vol. 277, Issue 28, 25823-25830, July 12, 2002
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From the Pediatric Liver Center and Liver Transplantation
Program, Section of Pediatric Gastroenterology, Hepatology, and
Nutrition, Department of Pediatrics, University of Colorado School of
Medicine, Denver, Colorado 80262 and The Children's Hospital,
Denver, Colorado 80218
Hydrophobic bile acids are toxic to isolated rat
hepatocytes by mechanisms involving mitochondrial dysfunction and
oxidative stress. In the current study we examined the role of nitric
oxide (NO), a potential mediator of apoptosis, during bile acid-induced apoptosis. Freshly isolated rat hepatocytes and hepatic mitochondria generated NO and peroxynitrite (ONOO
Nitric Oxide Ameliorates Hydrophobic Bile Acid-induced Apoptosis
in Isolated Rat Hepatocytes by Non-mitochondrial Pathways*
) in a
concentration- and time-dependent manner when exposed to the toxic bile salt glycochenodeoxycholate (GCDC) (25-500
µM), which was prevented by the nitric-oxide synthase
(NOS) inhibitors NG-monomethyl-N-arginine monoacetate
(L-NMMA) and 1400W. Relationships between hepatocyte NO
production and apoptosis were examined by comparing the effects of NOS
inhibitors with other inhibitors of GCDC-induced apoptosis. Inhibitors
of caspases 8 and 9, the mitochondrial permeability transition blocker
cyclosporin A, and the antioxidant idebenone reduced NO generation and
apoptosis in GCDC-treated hepatocytes. In contrast, NOS inhibitors had
no effect on GCDC-induced apoptosis despite marked reduction of NO and
ONOO. However, treatment with the NO donors
S-nitroso-N-acetylpenicillamine and spermine
NONOate
[N-(-aminoethyl)N-(2-hydroxy-2-nitrohydrazino)-1,2-ethylenediamine) inhibited apoptosis and caspase 3 activity while significantly elevating NO levels above GCDC-stimulated levels. Neither NO donors nor
NOS inhibitors affected GCDC-induced mitochondrial permeability transition or cytochrome c release from liver mitochondria
or GCDC-induced mitochondrial depolarization from isolated hepatocytes, suggesting that NO inhibits bile acid-induced hepatocyte apoptosis by a
non-mitochondrial-dependent pathway. In conclusion, whereas NO produced from GCDC-treated hepatocytes neither mediates nor protects
against bile acid-induced apoptosis, higher levels of NO inhibit
GCDC-induced hepatocyte apoptosis by caspase-dependent pathways.
*
This work was supported in part by National Institutes of
Health Grant RO1 DK-38446, the Abby Bennett Liver Research Fund, and
postdoctoral fellowship grants from the American Liver Foundation and
the Cystic Fibrosis Foundation (to B. Y.). This work was presented in
part at the 52nd annual meeting of the American Association for the
Study of Liver Diseases, November 9-13, 2001, Dallas, TX
(Gumpricht, E., Deveraux, M. W., Dahl, R., and Sokol, R. J. (2001) Hepatology 34, 272A (Abstr. 399)).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Box B290, The
Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218. Tel.: 303-861-6669; Fax: 303-764-8025; E-mail:
sokol.ronald@tchden.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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