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ToxSci Advance Access originally published online on June 16, 2004
Toxicological Sciences 2004 81(1):43-49; doi:10.1093/toxsci/kfh195
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Toxicological Sciences vol. 81 no. 1 © Society of Toxicology 2004; all rights reserved.

Enhancement of Hepatocarcinogenesis by Kojic Acid in Rat Two-Stage Models after Initiation with N-bis(2-hydroxypropyl)nitrosamine or N-diethylnitrosamine

Tamotsu Takizawa*,{dagger}, Toshio Imai*, Jun-ichi Onose*, Makoto Ueda*, Toru Tamura*, Kunitoshi Mitsumori*,{ddagger}, Keisuke Izumi{dagger} and Masao Hirose*,1

* Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan; {dagger} Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima, Tokushima 770-8503, Japan; and {ddagger} Laboratory of Veterinary Pathology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan

Received February 14, 2004; accepted May 26, 2004

Kojic acid (KA) has been used as a food additive for preventing enzymatic browning of crustaceans and as 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 proliferating cell nuclear antigen (PCNA) expression (3.8 ± 2.3 vs 2.6 ± 0.7 in the 0%) were significantly increased by the 2% treatment. The PCNA-positive hepatocytes were abundantly localized around the vacuolated and granulomatous legions in both experiments 1 and 2. In experiment 3, significant increases 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 were again observed with 2% KA. These results demonstrate tumor-promoting and possible hepatocarcinogenic activity of KA at 2%, but the carcinogenic potential is likely to be weak. This study also indicated that enhanced replication of hepatocytes related to toxic changes might be involved as an underlying mechanism.

Key Words: kojic acid; hepatocarcinogenesis; hepatic tumor promotion.


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