ToxSci Advance Access published online on June 16, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh195
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
* To whom correspondence should be addressed. E-mail: m-hirose{at}nihs.go.jp.
Kojic acid (KA) has been used as a food additive for preventing enzymatic browning of crustaceans and a cosmetic agent for skin whitening. In the present experiments, effects of KA on the induction of hepatic pre-neoplastic lesions in N-bis(2-hydroxypropyl)nitrosamine-initiated (experiment 1) and non-initiated (experiment 2) models, and its promoting influence in a medium-term liver bioassay (experiment 3) were investigated at dietary doses of up to 2% in male F344 rats. In experiment 1, 2% KA feeding induced significant increases in numbers (22.3±13.0 vs 8.5±3.4 in the 0%) and areas (0.37±0.29 vs 0.05±0.03 in the 0%) of glutathione-S-transferase P form (GST-P) positive foci and toxic changes such as
vacuolation of hepatocytes and microgranulomas. The development of GST-P-positive foci was pronounced in the animals with hepatocellular toxic changes. In experiment 2, numbers (0.65±0.57 vs 0.17±0.28 in the 0%) and areas (0.005±0.005 vs 0.0007±0.0012 in the 0%) of GST-P positive foci and hepatocellular PCNA expression (3.8±2.3 vs 2.6±0.7 in the 0%) were significantly increased by the 2% treatment. PCNA-positive hepatocytes were abundantly localized around the vacuolated and granulomatous legions in both experiments 1 and 2. In experiment 3, significant increase in numbers (16.9±3.2 vs 8.4±2.7 in the 0%) and areas (1.62±0.39 vs 0.77±0.34 in the 0%) of GST-P positive foci was again observed with 2% KA. These results demonstrated promoting and possible hepatocarcinogenic activity of KA at 2%, but carcinogenic potential is likely to be weak. It was indicated that enhanced replication of hepatocytes related to toxic changes might be involved in the underlying mechanisms.
Accepted May 26, 2004
Carcinogenicity
Enhancement of Hepatocarcinogenesis by Kojic Acid in Rat Two-Stage Models After Initiation with N-Bis(2-Hydroxypropyl)Nitrosamine or N-Diethylnitrosamine
2 Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
3 Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Laboratory of Veterinary Pathology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
4 Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
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