A number of biochemical events accompany the development of chronic liver disease and its evolution into hepatic cancer. Low plasma zinc and high plasma copper levels have been observed in individuals with advanced hepatocellular liver disease. Moreover, many investigators have demonstrated an increase in serum estradiol levels in individuals with chronic liver disease and hepatocellular carcinoma (HCC). In the present study, the relationship between these biochemical events and HCC was investigated in an animal model. Specifically, carbon tetrachloride (CCL4) was administered intragastrically to 20 female Sprague Dawley rats for 30 weeks. All 20 animals developed cirrhosis. Six (30%) developed HCC. Significantly higher serum estradiol, zinc and copper levels were observed in the rats developing HCC as compared with those with cirrhosis alone (P < or = 0.05, 0.01 and 0.001, respectively). A trend toward increased serum levels of progesterone, ALT and total bilirubin (0.1 > or = P < or = 0.05) was found in the animals developing HCC. No differences in serum testosterone and alkaline phosphatase levels were noted between animals with and without HCC. These studies demonstrate that in animals with experimental CCL4-induced cirrhosis and HCC serum levels of estradiol, zinc and copper are increased, as is the case in man.