The accumulation process of copper (Cu) in the liver and the following
metabolic disorder of Cu were examined in LEC rats, a mutant strain w
hich accumulates Cu with age and shows spontaneous acute hepatitis and
/or hepatoma. Cu concentration in the liver of female rats was similar
to 220 mu g/g liver at 2 weeks of age, decreased to 100 mu g/g liver
at 4-6 weeks, and then started to increase with age linearly to the hi
ghest concentration of 250 mu g/g liver at 16 weeks. Although the Cu l
evel expressed by concentration (mu g/g liver) decreased during weanin
g, it increased linearly with age when it was expressed by content (mg
/liver), indicating a constant and preferential accumulation of Cu in
the liver. Cu concentration stopped increasing at 16 weeks in the live
r, followed by a sudden decrease to 1/2 the highest level. Biological
markers (serum lactate dehydrogenase and glutamic-oxaloacetic transami
nase activities) for liver damage started to increase, together with t
he appearance of signs of jaundice, when Cu attained the highest conce
ntration. Distributions of Cu and zinc (Zn) in the supernatant fractio
n of the liver indicated that both metals were mostly distributed to m
etallothionein (MT) and, to a small extent, to superoxide dismutase on
a gel filtration column throughout the course of the experiments. Ser
um Cu concentration started to increase in a form of ceruloplasmin, to
gether with serum marker enzyme activities for liver damage, Cu concen
tration in the kidneys also started to increase after the increase of
serum Cu. The results indicate that Cu accumulates in the form of MT i
n the liver of LEC rats to a maximum level of similar to 250 mu g/g li
ver, and then decreases suddenly with the onset of acute hepatitis. Th
e maximum level seems to be related to the capacity of MT synthesis, a
nd acute hepatitis is assumed to occur when Cu accumulates beyond the
capacity. Serum Cu started to increase, from the abnormally low level,
when the metal accumulated beyond the capacity of MT synthesis in the
liver, and it was partly reabsorbed by the kidneys and the rest was e
xcreted into urine. Changes in iron and zinc levels were determined an
d discussed in relation to those of Cu.