Carcinogenic risk of copper gluconate evaluated by a rat medium-term liver carcinogenicity bioassay protocol.

Abstract

Carcinogenic risk and molecular mechanisms underlying the liver tumor-promoting activity of copper gluconate, an additive of functional foods, were investigated using a rat medium-term liver carcinogenicity bioassay protocol (Ito test) and a 2-week short-term administration experiment. In the medium-term liver bioassay, Fischer 344 male rats were given a single i.p. injection of N-nitrosodiethylamine at a dose of 200 mg/kg b.w. as a carcinogenic initiator. Starting 2 weeks thereafter, rats received 0, 10, 300 or 6,000 ppm of copper gluconate in diet for 6 weeks. All rats underwent 2/3 partial hepatectomy at the end of week 3, and all surviving rats were killed at the end of week 8. In the short-term experiment, rats were given 0, 10, 300 or 6,000 ppm of copper gluconate for 2 weeks. Numbers of glutathione S-transferase placental form (GST-P) positive lesions, single GST-P-positive hepatocytes and 8-oxoguanine-positive hepatocytes, and levels of cell proliferation and apoptosis in the liver were significantly increased by 6,000 ppm of copper gluconate in the medium-term liver bioassay. Furthermore, hepatic mRNA expression of genes relating to the metal metabolism, inflammation and apoptosis were elevated by 6,000 ppm of copper gluconate both in the medium-term liver bioassay and the short-term experiments. These results indicate that copper gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxidative stress and inflammatory and pro-apoptotic signaling statuses may participate in its underlying mechanisms.

• Authors: Masayoshi Abe, Koji Usuda, Seigo Hayashi, Izumi Ogawa, Satoshi Furukawa, Maki Igarashi, Dai Nakae
• Journal: Archives of toxicology (Arch Toxicol) Vol. 82 Issue 8 Pg. 563-71 (Aug 2008) ISSN: 0340-5761 [Print] Germany
• PMID: 18350280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Gluconates
• Metals
• Mt2A protein, rat
• RNA, Messenger
• 8-hydroxyguanine
• Guanine
• Metallothionein
• Glutathione Transferase

Topics

• Administration, Oral
• Animals
• Apoptosis (drug effects)
• Biological Assay
• Carcinogenicity Tests
• Carcinogens (classification, metabolism, toxicity)
• Cell Proliferation (drug effects)
• Diet
• Dose-Response Relationship, Drug
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Gluconates (classification, metabolism, toxicity)
• Glutathione Transferase (metabolism)
• Guanine (analogs & derivatives, metabolism)
• Hepatectomy
• Hepatocytes (drug effects, enzymology)
• Liver (drug effects, metabolism, pathology)
• Liver Neoplasms (chemically induced, enzymology, pathology)
• Male
• Metallothionein (genetics, metabolism)
• Metals (metabolism)
• Oxidative Stress (drug effects)
• Precancerous Conditions (chemically induced, enzymology, pathology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred F344