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

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

The Journal of clinical investigation (2009-05-14)
Robert Hanczko, David R Fernandez, Edward Doherty, Yueming Qian, Gyorgy Vas, Brian Niland, Tiffany Telarico, Adinoyi Garba, Sanjay Banerjee, Frank A Middleton, Donna Barrett, Maureen Barcza, Katalin Banki, Steve K Landas, Andras Perl
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Elastase from porcine pancreas, Type I, ≥4.0 units/mg protein
Sigma-Aldrich
Elastase from porcine pancreas, lyophilized powder, suitable for cell culture
Sigma-Aldrich
Elastase from porcine pancreas, Type IV, Protein 50-90 %, lyophilized powder, ≥4.0 units/mg protein (biuret)
Sigma-Aldrich
Elastase from human leukocytes, lyophilized powder, ≥50 units/mg protein (Bradford)
Sigma-Aldrich
Elastase from porcine pancreas, Type III, lyophilized powder, Protein 55-85 %, ≥4.0 units/mg protein