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Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.

ABSTRACT: Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.

SUBMITTER: Hanczko R

PROVIDER: S-EPMC2689120 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.

Hanczko Robert R Fernandez David R DR Doherty Edward E Qian Yueming Y Vas Gyorgy G Niland Brian B Telarico Tiffany T Garba Adinoyi A Banerjee Sanjay S Middleton Frank A FA Barrett Donna D Barcza Maureen M Banki Katalin K Landas Steve K SK Perl Andras A

The Journal of clinical investigation 20090511 6

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility t ...[more]

PMID: 19436114

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Project description:ObjectivesStudies of the use of IV N-acetylcysteine in the management of non-acetaminophen-induced acute liver failure have evaluated various dosing regimens. The only randomized trial studying this application described a 72-hour regimen. However, observational studies have reported extended duration until normalization of international normalized ratio. This study seeks to compare differences in patient outcomes based on IV N-acetylcysteine duration.DesignRetrospective cohort study.SettingMedical ICU at a large quaternary care academic medical institution and liver transplant center.PatientsAdult patients admitted to the medical ICU who received IV N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure.InterventionsPatients were divided into cohorts based on duration; standard duration of IV N-acetylcysteine was considered 72 hours, whereas extended duration was defined as continuation beyond 72 hours.Measurements and main resultsThe primary outcome was time to normalization of international normalized ratio to less than 1.3 or less than 1.5; secondary outcomes included all-cause mortality and transplant-free survival at 3 weeks. In total, 53 patients were included: 40 in the standard duration cohort and 13 in the extended duration. There were no major differences in baseline characteristics. There was no significant difference in time to international normalized ratio normalization between cohorts. Transplant-free survival was higher with extended duration (76.9% extended vs 41.4% standard; p = 0.03). All-cause mortality at 3 weeks was numerically lower in the extended duration group (0% extended vs 24.1% standard; p = 0.08).ConclusionsPatients with non-acetaminophen-induced acute liver failure who received extended duration N-acetylcysteine were found to have significantly higher transplant-free survival than patients who received standard duration, although there was no significant difference in time to normalization of international normalized ratio or overall survival. Prospective, randomized, multicenter study is warranted to identify subpopulations of patients with non-acetaminophen-induced acute liver failure who could benefit from extended treatment duration as a bridge to transplant or spontaneous recovery.

Dataset Information

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.

Publications

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.

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