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American Journal of Pathology, Vol 134, 1263-1274, Copyright © 1989 by American Society for Investigative Pathology

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Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis

S Toyokuni, S Okada, S Hamazaki, M Fujioka, JL Li and O Midorikawa
Department of Pathology, Faculty of Medicine, Kyoto University, Japan.

Rats intraperitoneally injected with a daily dose of cupric nitrilotriacetate (Cu-NTA), which contained 4 to 7 mg of copper/kg body weight, showed submassive liver necrosis, hemolytic anemia, and acute renal tubular necrosis at the beginning of the experiment and intermittently after 4 weeks of injections. All rats that survived over 8 weeks exhibited liver fibrosis with portal-portal, portal-central, and central-central bridging. In all rats that survived over 16 weeks, micronodular cirrhosis of the liver or extensive liver fibrosis was observed. The copper content of the cirrhotic/fibrotic liver was above 250 micrograms/g dry weight. Electron-microscopic x-ray analysis at day 93 revealed that copper stored in secondary lysosomes was always accompanied by a proportional amount of sulfur (correlation coefficient, 0.98; P less than 0.005). An experimental model of copper toxicosis in terms of copper-induced cirrhosis of the liver was established with exogenous copper chelated by nitrilotriacetate.