Studies on thyroid function in rats subjected to repeated oral administration with kojic acid.

Higa, Yoshitaka; Ohkubo, Atsushi; Kitajima, Shunichi; Hatori, Akiko; Kariya, Kimio

doi:10.2131/jts.25.3_167

Cited by 8 publications

(11 citation statements)

References 6 publications

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“…Histopathologically, decreased colloid in the follicles, and hypertrophy/diffuse hyperplasia were apparent in this group 13 . Inhibition of iodine uptake and organic iodine formation in the thyroid gland by kojic acid have also been recently reported by others 14,15 .…”

Section: Methodssupporting

confidence: 75%

Environmental Agents, Endocrine Disrupting Chemicals and Rat Thyroid Carcinogenesis

et al. 2001

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Thyroid cell proliferation caused by environmental compounds is well known to be associated promotion of carcinogenesis. For example, kojic acid, a secondary fungal metabolite, induces cell proliferation in rat thyroid follicular epithelium, and promotes thyroid carcinogenesis after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN). This was due to negative feedback through the pituitary-thyroid axis caused by inhibition of iodide uptake and iodine organification. Subcutaneous cholesterol pellets containing 17β-estradiol 3-benzoate also enhance rat thyroid carcinogenesis in ovariectomized female rats initiated with DHPN, although this was not the case with weak endocrine disrupting chemicals such as methoxychlor, atrazine and bisphenol A, which rather caused inhibition, possibly due to decrease in body weight gain. A high soybean diet enhances thyroid cell proliferation with increase in serum TSH level in synergism with a low iodine diet, presumably soybean diet primarily stimulate serum TSH release from the pituitary specifically under iodine deficiency conditions. (J Toxicol Pathol 2001; 14: 71-77)

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Section: Methodssupporting

confidence: 75%

Environmental Agents, Endocrine Disrupting Chemicals and Rat Thyroid Carcinogenesis

et al. 2001

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“…Recently, we have also reported thyroid weight gain and a morphological change, i.e., follicular epithelial hypertrophy, observed in the thyroid of rats orally administered KA for 4 weeks (Higa et al, 2000). In addition, increased 125 I uptake from blood into the thyroid was observed along with increased 125 I in the TCA-precipitation fraction in the thyroid gland.…”

Section: Introductionmentioning

confidence: 69%

“…In our previous study of oral administration for 4 weeks, in which rats were given 0, 4, 15, 62.5, 250 and 1,000 mg/kg of KA, we reported that the weight increase in the thyroid gland and a morphological change, i.e., hypertrophy of the thyroid follicular epithelial cells, were observed in the group given 1,000 mg/kg of KA (Higa et al, 2000). In addition, 125 I uptake from blood into the thyroid and the 125 I in the TCA-precipitate fraction in the thyroid were enhanced in those rats, while 125 I organification activity did not change.…”

Section: Discussionmentioning

confidence: 86%

“…Since KA influenced thyroidal function at 1,000 mg/kg dose in our previous repeat oral administration study for 4 weeks (Higa et al, 2000), we selected 1,000 mg/kg as the dose level in the present study. Rats were given single-dose administration of KA suspended in 0.5% carboxymethylcellulose (Wako Pure Chemical Industries Ltd., Inc., Osaka, Japan) solution orally through a plastic gastric tube.…”

Section: Administrationmentioning

confidence: 99%

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Effects of Kojic Acid on Thyroidal Functions in Rats by Single-Dose Administration and in Cultured Rat Thyroid Cells (Frtl-5 Cells)

Higa

Ohkubo

Kitajima³

et al. 2002

J. Toxicol. Sci.

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-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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“…With regard to carcinogenicity, despite some positive results in rodent thyroid, it was strongly indicated that thyroid carcinogenesis was due to negative feedback of the pituitary−thyroid axis following the inhibition of thyroxine synthesis caused by interference with iodine uptake and its organification due to a non-genotoxic mechanism (Higa et al, 2000;Tamura et al, 2001;Hirose et al, 2001;Higa et al, 2002;Tamura et al, 2006). On hepatocarcinogenesis, there were no findings suggesting carcinogenicity in mouse up to 1% KA treatment (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Kojic Acid -Absence of Tumor-Initiating Activity in Rat Liver, and of Carcinogenic and Photo-Genotoxic Potential in Mouse Skin

Higa¹,

Kawabe²,

Nabae³

et al. 2007

J. Toxicol. Sci.

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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.

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Studies on thyroid function in rats subjected to repeated oral administration with kojic acid.

Cited by 8 publications

References 6 publications

Environmental Agents, Endocrine Disrupting Chemicals and Rat Thyroid Carcinogenesis

Environmental Agents, Endocrine Disrupting Chemicals and Rat Thyroid Carcinogenesis

Effects of Kojic Acid on Thyroidal Functions in Rats by Single-Dose Administration and in Cultured Rat Thyroid Cells (Frtl-5 Cells)

Kojic Acid -Absence of Tumor-Initiating Activity in Rat Liver, and of Carcinogenic and Photo-Genotoxic Potential in Mouse Skin

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