Lack of Initiating Activity of Kojic Acid on Hepatocarcinogenesis in F344 Rats

Abstract

Kojic acid (KA) has been used as a food additive for preventing enzymatic browning of crustaceans and as a cosmetic agent for skin whitening. To date, it has been reported that female B6C3F1 mice receiving 3% KA in the diet were found to develop hepatocellular tumors, but the underlying mechanism of liver tumorigenicity is still not clear. In the present experiments, in order to investigate possible liver initiation activity, partially hepatectomized male F344 rats received a single oral dose of 0, 1000 and 2000 mg/kg body weight of KA followed by dietary administration of 0.015% of N-2-acetylaminofluorene (2-AAF) for 2 weeks and a single 0.8 mL/kg body weight dose of CCl4. Furthermore, male F344 rats were fed a diet containing 0 or 2% KA for 3, 7 and 28 days, and the 8-oxodeoxyguanosine (8-OxodG) levels in nuclear DNA were measured to examine the formation of oxidative DNA adduct and cell proliferating activities of hepatocytes in the liver. In the liver initiation assay, there were no significant differences in the number or area of glutathione S-transferase placental form (GST-P) positive foci, putative preneoplastic lesions, between the KA-treated and control groups. Cell proliferation of hepatocytes in rats given KA for 3 and 7 days was significantly increased as compared with the relevant control values, but no significant elevation in 8-OxodG levels was apparent. The results of the present study suggest that KA has neither liver initiation activity nor capability of 8-OxodG formation, but some evidences suggestive of liver tumor promoting effects in rats.