A MARKED INCREASE IN FREE COPPER LEVELS IN THE PLASMA AND LIVER OF LEC RATS - AN ANIMAL-MODEL FOR WILSON-DISEASE AND LIVER-CANCER

Most of copper present in rat plasma and liver binds to caeruloplasmin and metallothionein, respectively, and is not redox active. However, free forms of copper including loosely bound forms to other molecules are redox active. We assessed the free copper in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disea se and liver cancer. Compared to those of control rats, the liver and plasma of LEC rats showed a marked elevation of free copper, especiall y at the stage of acute hepatitis, in parallel with an increase of tot al copper levels in the livers and a decrease of plasma caeruloplasmin (ferroxidase I) activity. At the onset of jaundice, the total copper levels, however, decreased in liver, but increased in plasma, while fr ee copper levels in both liver and plasma remained higher. Free iron l evels in both liver and plasma were also determined and did not change significantly, except for the case of plasma in jaundiced rats. The d ata are consistent with a proposal in which increased levels of redox active free copper in the liver of LEC rats catalyze Fenton-type react ions, producing a large flux of hydroxyl radicals that would play an i mportant role in the observed liver dysfunction, leading to acute hepa titis, and, finally, hepatocarcinoma. This is the first demonstration that the free copper may participate in the pathophysiology of the LEC rats and Wilson disease.