Absence of liver tumor-initiating activity of kojic acid in mice

Moto, Mitsuyoshi; Mori, Takayoshi; Okamura, Miwa; Kashida, Yoko; Mitsumori, Kunitoshi

doi:10.1007/s00204-005-0034-4

Cited by 14 publications

(16 citation statements)

References 21 publications

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“…As a result, no tumor-initiating activity was observed following a single oral administration of 2,000 mg/kg of KA and the dietary administration of 2% KA for 28 days [52]. In the latter assay using ICR mice, treatment with diet containing 3% KA for 4 weeks also did not show any tumor-initiating activity [31]. From these results, the possibility that KA has an in vivo genotoxic potential is considered to be extremely low, although KA has a tumor-promoting activity in the liver of rodent species.…”

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confidence: 92%

Enhancement of Hepatocellular Proliferative Activity of Kojic Acid in Mice by a Simultaneous Administration of Ascorbic Acid

Kono

Moto

Muguruma

et al. 2007

The Journal of Veterinary Medical Science

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ABSTRACT. To examine the tumor modification activity of kojic acid (KA) by sodium ascorbic acid (AA), 5-week-old male ICR mice were administered intraperitoneally with N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after the initiation treatment, animals were fed basal diet containing 0 (Group 1: DEN alone) or 3% KA (Group 3: DEN+KA), drinking water containing 5,000 ppm AA (Group 2: DEN+AA) or 3% KA and 5,000 ppm AA (Group 4: DEN+KA+AA) for 6 weeks. One week after the administration of KA and/or AA, all mice were subjected to two-thirds partial hepatectomy. At the end of the experimental period, all surviving mice were sacrificed and removed the liver. The liver weights of the Groups 3 and 4 were significantly increased, and the number of proliferating cell nuclear antigen positive hepatocytes and the gene expressions of Ccnc, Ccnd1, Ercc and Cyp7a1 were significantly increased in the Group 4, as compared to the Group 1. These results of the present study suggest that AA enhances the hepatocellular proliferative activity of KA in mice. KEY WORDS: ascorbic acid, hepatocarcinogenesis, kojic acid, mouse.J. Vet. Med. Sci. 69(9): 899-908, 2007 Kojic acid (KA; 5-hydroxy-2(hydroxymethyl)-4-pyrone) is a secondary metabolic product of various species of Aspergillus and Penicillium [23]. It is known that this acid inhibits polyphenol oxidase (tyrosinase) in mushrooms, potatoes, apples and crustaceans [41]. Since polyphenol oxidase catalyzes the conversion of tyrosine to melanin via 3,4-dihydroxyphenylalanine and dopaquinone [21], KA has been used as an inhibitor of polyphenol oxidase in food additives for preventing enzymatic browning of raw crabs and shrimps. In addition, because of its excellent skin whitening properties [35] and inhibitory actions on human melanocyte tyrosinase [28], KA has been applied as a cosmetic agent for the purpose of skin lightening.It has been reported that hepatocellular tumors were induced in B6C3F1 mice that were fed diet containing 3% KA for 20 months [14]. In another study, diet containing 0, 1.5 or 3% KA was administered to heterozygous p53-deficient mice of the CBA strain [p53 (+/-) mice] and their wild-type littermates [p53 (+/+) mice] for 26 weeks [50]. In the study, the incidences of hepatocellular adenomas as well as altered hepatocellular foci were increased in p53 (+/-) and p53 (+/+) mice of KA-treated groups with and/or without initiation, as compared to those in the untreated control mice. In our previous confirmation study using CBA wildtype mice, the incidence of proliferative lesions was significantly increased in the liver of mice that were fed diet containing 1% KA for 26 weeks [51]. In addition, it has recently been reported that a 20-week dietary administration of 2% KA increases the number and area of glutathione Stransferase placental (GST-P) form positive foci in the liver of F344 rats [49]. These findings suggest the hepatocarcinogenic potential of KA in the liver of rodent species.With regard to the genotoxicity of KA, several in vitro genotoxici...

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confidence: 92%

Enhancement of Hepatocellular Proliferative Activity of Kojic Acid in Mice by a Simultaneous Administration of Ascorbic Acid

Kono

Moto

Muguruma

et al. 2007

The Journal of Veterinary Medical Science

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“…From these findings, the authors reported that KA has neither liver initiation activity nor capability of 8-OxodG formation. In addition, KA did not exert initiation activity in mouse liver in the tumor initiation test (Moto et al, 2006). In this report, the authors noted that all the studies performed in mouse or rat livers until now suggested possible KA tumorpromotion activity, and it is speculated that the carcinogenic potential of KA is related to tumor-promoting activity more closely than tumor-initiating activity.…”

Section: Genotoxicity and Carcinogenicity Of Ka In Rat Livermentioning

confidence: 88%

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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“…During preparation of this manuscript it has been reported in a two step carcinogenesis study, in which mice were fed a diet containing 3z KA at initiation step and phenobarbital was used as a tumor promoter, that there is no liver tumor initiating activity (19). At present, it is not clear whether the partial hepatectomy which was performed two weeks after the beginning of phenobarbital administration was at an appropriate time to detect initiating activity of KA or not.…”

Section: Discussionmentioning

confidence: 99%

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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Absence of liver tumor-initiating activity of kojic acid in mice

Cited by 14 publications

References 21 publications

Enhancement of Hepatocellular Proliferative Activity of Kojic Acid in Mice by a Simultaneous Administration of Ascorbic Acid

Enhancement of Hepatocellular Proliferative Activity of Kojic Acid in Mice by a Simultaneous Administration of Ascorbic Acid

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

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

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