Copper toxicosis and tolerance in the rat. II. Tolerance--a liver protective adaptation.

Copper tolerance was induced in rats to determine the effective dose, duration and subsequent response to copper challenge on liver copper and associated changes. Male weanling rats were fed powdered diets supplemented with copper as follows: a) 3000, 4000, 5000 and 6000 mg/kg Cu for 15 weeks, b) 3000 mg/kg Cu for 52 weeks, c) 6000 mg/kg Cu for 3 weeks to animals which had previously received either 3000 mg/kg Cu or the control diet (10-20 mg/kg Cu) for 15 weeks. Animals in Groups (a) and (b) were weighed and killed at regular intervals. All livers were examined histologically and by Atomic Absorption Spectroscopy for copper. Animals on the copper-supplemented diets accumulated copper in the liver with associated damage. Subsequently, in rats receiving up to 5000 mg/kg copper, liver copper concentration declined, regeneration occurred, growth resumed and the animals became tolerant. This adaptation continued for 52 weeks in animals on 3000 mg/kg copper with an inverse correlation between body weight and liver copper concentration. Rats on 6000 mg/kg copper maintained their hepatic overload and did not recover. Copper primed animals were less susceptible to a test dose of Cu than previously unchallenged animals. Tolerance to high dietary copper can be invoked within a dose range determined by the level of previous exposure. The adaptation is liver-sparing and involves the progressive readjustment of copper homeostasis.