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-Kojic acid (KA) has been widely used as a quasi-drug ingredient. Possible promotion activity of KA was suggested on livers of mouse and rat by findings obtained in genotoxicity and carcinogenicity studies performed thus far. Therefore, in order to examine safety as a quasi-drug ingredient, we investigated the presence of initiation activity in rat liver and the photo-genotoxicity and carcinogenicity in mouse skin. In medium-term carcinogenesis test in rats, 2.0% KA was orally given to F344/ DuCrj rats for 4 weeks of the initiation period, followed by the combination of partial hepatectomy and treatment with a hepatocarcinogenesis promoter, phenobarbital (PB). As a result, glutathione S-transferase placental form (GST-P) positive foci of 0.2 mm or more in diameter in the KA group, which is usually used in determination of pre-cancerous lesions, did not increase significantly in both numbers and areas compared with those of the non-initiated controls. In the concurrent analysis, however, numbers of GST-P-positive foci of two cells or more and 0.1 mm or more in diameter increased slightly, and possible weak initiation activity of KA was equivocal. However, considering the known fact that KA exerts promotion activity in the liver of F344 rats by long-term dietary administration, it was suggested that the observed slight increase of the numbers of GST-P-positive foci in rat liver was the effect of promotion activity of KA rather than the initiation activity. In DNA adducts formation assay in a rat liver, no clear adducts derived from KA were detected in male F344/DuCrj rats administered 0.5% or 2% KA orally, and KA was considered not to form DNA adducts in rat liver. In the in vitro photo-reverse mutation assay with bacteria, KA exerted weak photo-mutagenicity. Furthermore, in chromosome aberration study in Chinese hamster lung cells (CHL/IU cells) with UV irradiation, KA induced chromosome aberration at high-dose (1.4 mg/mL) treatment with UV irradiation, but was negative without UV irradiation. However, in the in vivo photo-micronucleus study in mouse, in which 1.0 or 3.0% KA containing cream was applied twice to the back of the animals with a 24-hr interval, KA did not induce micronuclei in mouse epidermal cells. Based on these results, it is considered that the risk of KA to exert photo-carcinogenicity is quite low in the skin. In skin carcinogenesis bioassay for initiation-promotion potential, 3.0% KA cream formulation was applied to the back of the mouse for 1 week (once a day, total 7 times) and for 19 weeks (5 times a week, total 95 times) during the initiation and the promotion stages, respectively. No skin nodules were observed in any animal skins formed due to KA treatment given in either stage. Therefore, KA is consid- ered not to possess initiation nor promotion activity of skin carcinogenesis. Furthermore, from the above findings, it is suggested that KA is virtually safe as a quasi-drug ingredient.

To elucidate the effects of kojic acid on thyroid function, the compound was given orally to male rats for 4 weeks at 0, 4, 15, 62.5, 250 and 1,000 mg/kg. In 1,000 mg/kg treatment of kojic acid, the rats showed a slight decrease in motility, inhibition of body weight gain, and a decrease in food consumption. An increase in thyroid weight and a morphological change, i.e., hypertrophy of epithelial cells of the thyroid gland follicles, were observed after 1 week of administration. In addition, the uptake of radioactive iodine from blood into the thyroid gland was enhanced and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. However, the rates of the iodination in the thyroid gland did not change during the experiment period. Although serum T4 concentration was low in the rats treated with 1,000 mg/kg kojic acid, it was not observed in any changes in TSH concentration. None of these changes were found in the other groups. These observations suggest that massive administration of kojic acid may decrease blood T4 concentration and that thyroid function may be enhanced compensatorily. On the other hand, the absorption of kojic acid was rapid as manifested by the Tmax of blood concentrations of radioactivity, which was as short as 1.0 +/- 0.0 hr, and the t1/2 was 4.8 +/- 0.3 hr. Blood concentrations of radioactivity disappeared nearly completely at 24 hr after administration. This result indicates that the toxic effect observed on the thyroid gland treated with only the largest dosage of kojic acid may depend on a fast decrease following a transient increase of concentration of the compound in the blood.

-The effects of kojic acid (KA) on thyroidal function were studied by single-dose administration in rats and in cultured rat thyroid cells . In rats receiving a single dose of 1,000 mg/kg KA orally, the 125 I uptake from blood into the thyroid gland was significantly lower than that of the control group from 30 min to 24 hr after administration. The 125 I organification activity of the KA groups was significantly lower than control from 30 min to 6 hr after administration. However, the 125 I organification activity at 24 hr or 48 hr after administration recovered enough to be nearly comparable with the control group. In the study in FRTL-5 cells, KA inhibited iodine organification dose-dependently, but did not inhibit iodine uptake. These results suggest that the observed lower iodine uptake activity in the single-dose administration study in rats was due to the inhibition of iodine organification caused by the oral administration of KA, consequently decreasing iodine in the entire thyroid gland.Although serum T4 showed a tendency to decrease from 2 hr to 48 hr after administration of KA, serum TSH did not show any evident change associated with KA in the single-dose administration study in rats. Based on these results, it is presumed that a massive dose or long administration period might be needed to decrease serum T4 and increase serum TSH.From these results, it is presumed that KA affected thyroidal function when given at a massive dose or in a long administration period by inhibiting iodine organification in the thyroid.

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