Role of copper accumulation in spontaneous renal carcinogenesis in Long-Evans Cinnamon rats

Spontaneous renal cell tumors in totals of 223 male and female Long-Evans C innamon (LEC) rats of 51-120 weeks old, 157 male F334 rats of 51-120 weeks old, and 14 male Long-Evans Agouti (LEA) rats of 51-70 weeks old were exami ned histologically. The incidences of renal cell tumors increased with age in male and female LEC rats, but no tumors developed in F344 or LEA rats. D ilated atypical tubules of the kidneys were observed at high incidence in a ged LEC rats. Copper staining of LEC rat kidneys showed a positive reaction in proximal tubules of the cortex and the outer stripe of the medulla. The renal copper concentration of LEC rats reached a peak in the period of nec rotizing hepatitis with renal tubular necrosis, and was higher than that in F344 rats for up to 106 weeks. In contrast, the renal iron concentration o f LEC rats was lower than that in F344 rats except in the period of necroti zing hepatitis. Long-term treatment of LEC rats with D-penicillamine, a cop per-chelating agent, inhibited accumulation of copper, but not iron, in the kidneys, and inhibited the development of karyomegaly of proximal tubules and dilated atypical tubules. These results suggest that persistent copper accumulation after toxic necrosis of tubules is the major cause of spontane ous renal carcinogenesis in LEC rats.