Hepatic hyperplasia and cancer in rats: alterations in copper metabolism

We previously demonstrated that rats exposed to the peroxisome proliferator (PP) diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxi dase activity, which suggests tissue copper deposition. Copper is highly to xic in excess, and results in cellular damage and hepatocellular carcinomas (HCC). This study addresses changes in expression of copper-related genes and metal accumulation in hyperplastic liver and tumors induced by PP, Male rats were fed diets containing DEHP or clofibrate (CLF) for 3-60 days (hyp erplasia) and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-beta-hydroxyet hyl) acetamide for 10 months (HCC), During hyperplasia, an immediate and pr ogressive decrease in serum CP activity was observed (P < 0.05), as mere re ductions in mRNA levels for both CP and Wilson's disease gene (WD gene, a P -type ATPase) (P < 0.05), Tumor-bearing rats had lower serum CP activity (P < 0.05), and CP and WD gene mRNA levels were reduced in tumors (P < 0.05), and in liver surrounding tumors (SL) (P < 0.05), Metallothionein mRNA show ed no consistent changes during hyperplasia. Tumors showed a 2.5-fold induc tion of metallothionein mRNA (P < 0.05), and a 1.2-fold increase in SL. Tem poral increases in liver copper content occurred during hyperplasia, with i ncreases of 2-fold (DEHP) and 3.3-fold (CLF) at 60 days (P < 0.05), Copper content was 2,2-fold higher in tumors (P < 0.05) and 1.7-fold higher in SL; iron did not increase and zinc decreased temporally. Thus, copper accumula tion and changes in copper-related gene expression may be contributing fact ors in liver neoplasia in PP-treated rats. Loss of CP results in decreased free radical scavenger capacity and thus may enhance oxidative damage induc ed by PPs.