1. ¹Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
2. ²Department of Pathology, University of Wisconsin, Madison, WI 53706, USA
3. ³Pathology Service, VA Hospital, Madison, WI 53705, USA
4. ⁴Department of Cellular and Structural Biology, UTHSC, San Antonio, TX 78229, USA
5. ⁵Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, USA
6. ⁶Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN 37232, USA
7. ⁷GRECC, Audie Murphy VA Hospital, San Antonio, TX 78229, USA
8. ⁸Department of Pediatrics, University of California, San Francisco, CA 94341, USA
9. ⁹GRECC, Palo Alto VA Health Care System, Palo Alto, CA 94304, USA

Correspondence: T-T Huang, Department of Neurology and Neurological Sciences, Stanford University, 3801 Miranda Ave., Bldg 100, Room D3-101, mail stop 154-I, Palo Alto, CA 94304, USA. E-mail: tthuang@stanford.edu

Received 15 June 2004; Revised 14 September 2004; Accepted 14 September 2004; Published online 8 November 2004.

Abstract

Mice deficient in CuZn superoxide dismutase (CuZnSOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1-/- mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1-/- and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1-/- mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.