Insights into disease-specific mechanisms for liver repopulation are needed for
cell therapy. To understand the efficacy of
pro-oxidant hepatic perturbations in
Wilson disease, we studied Long-Evans Cinnamon (LEC) rats with
copper toxicosis under several conditions. Hepatocytes from healthy Long-Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of
copper to below 250 microg/g liver, presence of
ATPase, Cu++ transporting, beta
polypeptide (atp7b)
messenger RNA (
mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic
bile salt,
cholic acid, or liver radiation before
cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial
hepatectomy followed by
cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus
cholic acid followed by
cell transplantation was most effective, with cure in 75%, P < 0.001. As a group,
cell therapy cures in rats preconditioned with liver radiation plus
cholic acid resulted in less hepatic
copper, indicating greater extent of liver repopulation. We observed increased hepatic
catalase and
superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or
cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and
cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that
pro-oxidant perturbations were uniquely effective for
cell therapy in
Wilson disease because of the nature of preexisting hepatic damage.