Carcinogenic risk of copper gluconate evaluated by a rat medium-term liver carcinogenicity bioassay protocol.
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.
Abe
Masayoshi
M
Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Industries Limited, Saitama, Japan. abem@nissanchem.co.jp
Usuda
Koji
K
Hayashi
Seigo
S
Ogawa
Izumi
I
Furukawa
Satoshi
S
Igarashi
Maki
M
Nakae
Dai
D
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000145:classification / Q000378:metabolism / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004032:Diet; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005942:Gluconates / Q000145:classification / Q000378:metabolism / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D005942:Gluconates; D008670:Metals; C491055:Mt2A protein, rat; D012333:RNA, Messenger; C024829:8-hydroxyguanine; D006147:Guanine; D008668:Metallothionein; D005982:Glutathione Transferase