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

• Published in: Archives of toxicology 2008-08, Vol.82 (8), p.563-571
• Main Authors: Abe, Masayoshi, Usuda, Koji, Hayashi, Seigo, Ogawa, Izumi, Furukawa, Satoshi, Igarashi, Maki, Nakae, Dai
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Apoptosis; Apoptosis - drug effects; Bioassays; Biological Assay; Biomedical and Life Sciences; Biomedicine; Carcinogenicity Tests; Carcinogens; Carcinogens - classification; Carcinogens - metabolism; Carcinogens - toxicity; Cell Proliferation - drug effects; Copper; Diet; Dose-Response Relationship, Drug; Environmental Health; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genotoxicity and Carcinogenicity; Gluconates - classification; Gluconates - metabolism; Gluconates - toxicity; Glutathione Transferase - metabolism; Guanine - analogs & derivatives; Guanine - metabolism; Hepatectomy; Hepatocytes - drug effects; Hepatocytes - enzymology; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Neoplasms - chemically induced; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; Male; Metallothionein - genetics; Metallothionein - metabolism; Metals - metabolism; Occupational Medicine/Industrial Medicine; Oxidative Stress - drug effects; Pharmacology/Toxicology; Precancerous Conditions - chemically induced; Precancerous Conditions - enzymology; Precancerous Conditions - pathology; Rats; Rats, Inbred F344; Risk factors; RNA, Messenger - metabolism; Rodents; Toxicology
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-008-0294-x

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.