Carcinogenicity of kojic acid in rodents
2003 年 2003 巻 Suppl3 号 p. 59-67
詳細
2003 年 2003 巻 Suppl3 号 p. 59-67
Kojic acid, 5-hydroxy-2-(hydroxymethyl)-4-pyrone, is a secondary fungal metabolite commonly produced by Aspergillus and Penicillium. It is used in skin care product as a whitening agent, as a protectant against u.v. light, and as a food additive to prevent enzymatic browning of raw crabs and shrimps. Carcinogenicity of kojic acid in the thyroid gland of male and female B6C3F1 mice (at doses of 1.5% and 3% in diet) and weak tumorigenicity in the liver of female mice (at a dose of 3% in diet) was demonstrated on 1998. Since that time many experiments have been conducted for the risk assessment of this compound. Kojic acid, at doses higher than 0.03% in diet, promoted rat thyroid carcinogenesis in the 2-stage carcinigenesis assay initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). It induced diffuse hypertrophy and focal hyperplasia in rat follicular cells without prior initiation treatment, also indicative of tumorigenicity. Since genotoxicity of kojic acid is highly suspected, mechanistic approaches are important for the regulation of this compound. Several experiments have shown serum T4 levels to be decreased and TSH levels were markedly increased by the kojic acid treatment, pointing to a negative feedback mechanism through the pituitary-thyroid axis exists. This was shown to be due to the inhibition of iodine uptake and iodine organification in the thyroid rather than to increase in the liver T4-UDP-GT. Treatment with 2 % kojic acid for 8 weeks in the initiation period, followed by the thyroid promoter sulfodimethoxine (SDM) failed to demonstrate any initiation activity in the rat thyroid. Therefore, it is suggested that thyroid tumors were induced through non-genotoxic mechanisms. Kojic acid induced adenomas in heterozygous p53-deficient CBA [p53(+/-)] mice, susceptible to genotoxic carcinogens, as well as in wild mice at dietary doses of 1.5% and 3% for 26 weeks, in addition to cell proliferation, which is a marker for non-genotoxic carcinogens. The incidences of neoplastic as well as preneoplastic lesions were significantly greater in the p53(+/-) than in the wild-type mice. Kojic acid at a dose of 2% in diet promoted rat hepatocarcinogenesis in the medium-term liver assay and induced GST-P positive foci without initiation treatment. Therefore, kojic acid is suggested to be a hepatocarcinogen in both mice and rats, with probable involvement of genotoxicity in addition to non-genotoxic mechanism.
