Journal Article

Hepatic hyperplasia and cancer in rats: alterations in copper metabolism

Patricia K. Eagon, Annette G. Teepe, Mary S. Elm, Stasa D. Tadic, Marilyn J. Epley, Bonnie E. Beiler, Hisashi Shinozuka and Kalipatnapu N. Rao

in Carcinogenesis

Volume 20, issue 6, pages 1091-1096
Published in print June 1999 | ISSN: 0143-3334
Published online June 1999 | e-ISSN: 1460-2180 | DOI:
Hepatic hyperplasia and cancer in rats: alterations in copper metabolism

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We previously demonstrated that rats exposed to the peroxisome proliferator (PP) diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxidase activity, which suggests tissue copper deposition. Copper is highly toxic 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 (hyperplasia) and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-β-hydroxyethyl) acetamide for 10 months (HCC). During hyperplasia, an immediate and progressive decrease in serum CP activity was observed (P < 0.05), as were reductions 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 showed no consistent changes during hyperplasia. Tumors showed a 2.5-fold induction of metallothionein mRNA (P < 0.05), and a 1.2-fold increase in SL. Temporal increases in liver copper content occurred during hyperplasia, with increases 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 accumulation and changes in copper-related gene expression may be contributing factors in liver neoplasia in PP-treated rats. Loss of CP results in decreased free radical scavenger capacity and thus may enhance oxidative damage induced by PPs.

Keywords: BR931, 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-β-hydroxyethyl) acetamide; CLF, clofibrate; CP, ceruloplasmin; DEHP, di(2-ethylhexyl)phthalate; HCC, hepatocellular carcinoma; LEC, Long–Evans Cinnamon rats; MT, metallothionein; PP, peroxisome proliferator; WD gene, Wilson's disease gene or Atp7b in rat.

Journal Article.  5535 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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