Induction of Thyroid Tumours in(C57BL/6N×C3H/N)F1 Mice by Oral Administration of Kojic Acid

Fujimoto, Nariaki; Watanabe, Hisako; Nakatani, Toshio; Roy, Goutam; Ito, Akihiro

doi:10.1016/s0278-6915(98)00030-1

Cited by 66 publications

(65 citation statements)

References 9 publications

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“…A number of melanin synthesis inhibitors, including arbutin (hydroquinone--D-glucopyranoside) and kojic acid, have been used as cosmetic additives. [30][31][32][33] However, there is a continuing need to find more effective skin-whitening agents. Our results here indicate that the E. mollis extract is a useful depigmenting agent that has no cytotoxic effects, at least on B16 murine melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Elephantopus mollis H.B. and K. Extract on Melanogenesis in B16 Murine Melanoma Cells by Downregulating Microphthalmia-Associated Transcription Factor Expression

Hasegawa

Furuya

Mizuno

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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In this study, the inhibitory effect of Elephantopus mollis H.B. and K. extract on melanogenesis in B16 murine melanoma cells was examined and possible mechanisms were elucidated. The melanin content in B16 cells decreased when they were treated with E. mollis extract. Inhibition was accompanied by reduced expression of tyrosinase (TYR) and tyrosinaserelated protein 1 (TRP1). Furthermore, the expression level of microphthalmia-associated transcription factor (MITF), a major transcriptional regulator of genes encoding melanogenic enzymes such as Tyr and Trp1, decreased as assessed by western blotting and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These results suggest that E. mollis extract reduces melanogenesis by downregulating Mitf expression, leading to reduced expression of Tyr and Trp1. In addition, melanocortin-1 receptor (MC1R) expression was downregulated by E. mollis extract, suggesting desensitization to -melanocyte-stimulating hormone ( -MSH) of cells treated with the extract.

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Elephantopus mollis H.B. and K. Extract on Melanogenesis in B16 Murine Melanoma Cells by Downregulating Microphthalmia-Associated Transcription Factor Expression

Hasegawa

Furuya

Mizuno

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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“…Although kojic acid is not used as a food additive now, it is mainly used as a cosmetic agent for skin whitening properties (6,7) because of its inhibitory actions on human melanocyte tyrosinase (8). Kojic acid which is known to be genotoxic without microsomal activation, inducing mutation in bacteria and mammalian cells, chromosome aberrations in mammalian cells, and DNA damages detected by comet assay in mammalian cells (9,10) has been reported to induce hepatic tumors in mice (11), although no long-term carcinogenesis studies in rats have been reported. The initiation activity in the liver has been investigated in two step carcinogenesis studies of rats and mice.…”

Section: Introductionmentioning

confidence: 99%

In vivo Genotoxic Potential of Kojic Acid in Rodent Multiple Organs Detected by the Comet Assay

Kawaguchi

Nakamura

Honda

et al. 2008

Genes and Environment

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Kojic acid has been used for skin whitening as a cosmetic agent. Kojic acid is believed to be hepatocarcinogenic in mice. We conducted the comet assay in mouse and rat multiple organs to evaluate its in vivo genotoxic potential. Kojic acid induced dose-dependent DNA damage in ddY mouse stomach and liver and in Wistar rat stomach, liver, lung, and bone marrow after a single gavage administration at ≦1000 mg/kg. Its hepatic genotoxicity detected by the comet assay seems to contradict to absence of its hepatic tumor initiating activity revealed by the two-step carcinogenesis studies with mice and rats. However, considering the possibility that the sensitivity of the two-step carcinogenesis studies performed are not high enough to detect weak initiating activity of a chemical, it would be premature to conclude that its hepatic genotoxicity contradicts to the absence of initiating activity. In mice fed a diet containing 3% kojic acid for up to 10 days, DNA migration increased in the stomach after feeding for 2 days but it did not increased after feeding for 1 day and ≧4 days. In the colon, DNA migration after feeding of 3% kojic acid for 2 days was higher than the control values, but this increase was not statistically signiˆcant. In the stomach and colon, any statistically signiˆcant increases in DNA migration were not observed after feeding of 1.5% kojic acid. In the liver, DNA migration increased with feeding period and the increases after feeding of 3% and 1.5% kojic acid for ≧4 days and 6 days, respectively, were statistically signiˆcant. Our present results suggested good correlation between hepatocarcinogenicity of kojic acid and increasing tendency of its hepatic genotoxicity with dosing period when it is given to mice continuously in the diet.

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“…KA had been reported to induce hepatomas and thyroid adenomas in mice (7). Thyroid adenomas or hyperplasia production in the mouse or rat was suggested to be due to promoting activity of KA (7)(8)(9). In contrast, the possibility of involvement of genotoxicity of KA in mouse hepatoma development could not be excluded (10).…”

Section: Introductionmentioning

confidence: 99%

“…It was also found to be genotoxic in vivo, inducing micronuclei (MN) in peripheral blood of rats (6). KA had been reported to induce hepatomas and thyroid adenomas in mice (7). Thyroid adenomas or hyperplasia production in the mouse or rat was suggested to be due to promoting activity of KA (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…Since KA is a fungal product, soy sauce, miso and sake were suspected to contain KA. Out of 32 samples of fermented foods examined for the presence of KA, three samples were found to be positive, but the levels were not so high, being at the maximum, 1 ppm (personal communication by Dr. Tamio Maitani, National Health Sciences, Tokyo, Japan, Dec. 7,2005). Further, KA is still used in cosmetics as a skin lightening agent (quasi-drug) at concentrations of up to 1.5z due to its inhibiting action on human melanocyte tyrosinase (11).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Genotoxicity of Kojic Acid by Mutagenicity in Salmonella and Micronucleus Induction in Rodent Liver

Ishikawa

Sasaki

Kawaguchi

et al. 2006

Genes and Environment

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Three lots of kojic acid (KA) which were produced for use as a reagent, food additive and in cosmetics were shown to be mutagenic in S. typhimurium TA100 with or without S9 mix, with a speciˆc activity of around 100 revertants per mg of KA. Since there are contradictory reports on genotoxicity of KA, we examined, using HPLC, whether the mutagenicity to S. typhimurium is due to KA itself, or due to contaminants present in the KA samples. Although two UV absorbing fractions were separated by HPLC, mutagenicity was detected only in the major fraction and the speciˆc mutagenic activity of KA did not change before and after HPLC separation. The material in the major peak fractions on HPLC was conˆrmed to be KA by NMR. Thus it was demonstrated that KA itself is mutagenic and no mutagenic contaminants were detected in the three lots of samples. Since KA is known to produce liver tumors in mice, we further examined the genotoxicity of KA in the liver of rodents. KA induced micronuclei (MN) in the regenerating liver of adult mice by its gastric intubation at 1 g per kg body weight. However, no MN were induced in young mice (3 weeks old) without partial hepatectomy. Since it was recently found that KA had no tumor-initiating activity in the liver of mice in a two-step carcinogenicity study, there is no evidence that the genotoxicity detected in the mouse liver is involved in liver carcinogenesis.

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Induction of Thyroid Tumours in(C57BL/6N×C3H/N)F1 Mice by Oral Administration of Kojic Acid

Cited by 66 publications

References 9 publications

Inhibitory Effect of Elephantopus mollis H.B. and K. Extract on Melanogenesis in B16 Murine Melanoma Cells by Downregulating Microphthalmia-Associated Transcription Factor Expression

Inhibitory Effect of Elephantopus mollis H.B. and K. Extract on Melanogenesis in B16 Murine Melanoma Cells by Downregulating Microphthalmia-Associated Transcription Factor Expression

In vivo Genotoxic Potential of Kojic Acid in Rodent Multiple Organs Detected by the Comet Assay

Characterization of Genotoxicity of Kojic Acid by Mutagenicity in Salmonella and Micronucleus Induction in Rodent Liver

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