Lack of Initiating Activity of Kojic Acid on Hepatocarcinogenesis in F344 Rats

Watanabe, Takao; Mori, Takayoshi; Kitamura, Yasuki; Umemura, Takashi; Okamura, Miwa; Kashida, Yoko; Nishikawa, Akiyoshi; Hirose, Masao; Mitsumori, Kunitoshi

doi:10.1293/tox.18.79

Cited by 7 publications

(11 citation statements)

References 34 publications

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“…On the other hand, in vivo studies, bone marrow micronucleus tests in NMRI and ICR mice, dominant lethal test in mice and mutation test in Muta (CD2-lacZ80/ HazfBR) mice were negative [34]. In addition to these results, the in vivo liver initiation activity in F344 rats and ICR mice were negative [52]. Regarding the carcinogenicity of KA, it has been reported that hepatocellular tumors were induced in B6C3F1 mice fed diet containing 3% KA for 20 months [14], p53 (+/-) mice fed diet containing 1.5 or 3% KA for 26 weeks [48], and CBA wild-type mice fed diet containing 1% KA for 26 weeks [51].…”

Section: Discussionmentioning

confidence: 95%

“…In the former assay using F344 rats, we investigated the 8-oxodeoxyguanosine (8-OxodG) levels, a marker of DNA damage, in the liver. 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].…”

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confidence: 94%

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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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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 94%

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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“…In the liver initiation test for hepatocarcinogenicity in rats reported by Watanabe et al (Watanabe et al, 2005b), partially hepetectomized male F344 rats received a single oral dose of 0, 1000 and 2000 mg/kg body weight of KA followed by dietary administration of 0.015% of 2-AAF for 2 weeks and a single 0.8 mL/ kg body weight dose of CCl 4 , did not achieve significant differences in the numbers of GST-P-positive foci and putative preneoplastic lesions compared with the control groups. Furthermore, when male F344 rats receiving 0 or 2% KA for 3, 7 or 28 days were measured for 8-oxodeoxyguanosine (8-OxodG) levels in Table 11.…”

Section: Genotoxicity and Carcinogenicity Of Ka In Rat Livermentioning

confidence: 99%

“…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. Given that (1) partially hepatectomized animals received a single oral dose of KA as the initiation treatment in the rat liver initiation test for hepatocarcinogenicity (Watanabe et al, 2005b), while the animals received KA in diet for 4 weeks from Day 1 in the present study, and (2) it is known that KA exerts promotion activity in rat liver by long-term dietary administration in F344 rats as Watanabe et al reported, 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 the DNA adducts formation study, no spots of DNA adducts were detected in the liver of male F344/DuCrj rats receiving 0.5% or 2.0% KA orally for 7 or 28 days, suggesting KA does not form DNA adducts in rat liver.…”

Section: Genotoxicity and Carcinogenicity Of Ka In Rat Livermentioning

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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“…Furthermore, male F344 rats were fed diet containing 0 or 2% KA for 3, 7 and 28 days, and the 8-oxodeoxyguanosine (8-OxodG) levels in nuclear DNA were measured to examine the formation of oxidative DNA adduct and cell proliferating activities of hepatocytes in the liver were measured 16 . As a result, we found that KA does not have any liver initiation activity or capability of 8-OxodG formation, but some evidence was suggestive of liver tumor promoting effects in rats.…”

Section: Introductionmentioning

confidence: 99%

Induction of Hepatocellular Proliferative Lesions in CBA Mice by a 26-week Dietary Administration of Kojic Acid

et al. 2005

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In our previous study in which diets containing 0, 1.5 or 3% Kojic acid (KA) were administered to heterozygous p53-deficient mice of the CBA strain [p53 (+/-) mice] and their wild-type littermates [p53 (+/+) mice] for 26 weeks, the incidences of hepatocellular adenomas as well as altered hepatocellular foci were increased in p53 (+/-) and p53 (+/+) mice of the KA treated groups without initiation, as compared to those in the untreated control mice. In order to confirm the reproducibility of the induction of hepatocellular proliferative lesions in p53 (+/+) mice given KA, male CBA mice were given dietary administration of 0, 0.5, 1 or 2% KA for 26 weeks. Body weight gain in the 2% KA group was depressed after week 20 as compared to the corresponding control group. Significant increases of absolute and relative liver weights were observed in the groups treated with 1% and 2% KA. The incidences of hepatocellular adenomas in the control and 0.5, 1 and 2% KA groups were 5, 17, 10 and 21%, respectively, and those of hepatocellular foci in these groups were 15, 39, 45 and 47%, respectively, the difference between the control and 2% KA groups being statistically significant. The mean values for multiplicity of hepatocellular adenomas in the control and 0.5, 1 and 2% KA groups were 0.05, 0.2, 0.2 and 0.2, respectively, and those for hepatocellular foci were 0.2, 0.6, 0.8 and 0.6, respectively. The results of the present study suggest that KA has a hepatocarcinogenic potential in CBA mice. (J Toxicol Pathol 2005; 18: 159-165)

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Lack of Initiating Activity of Kojic Acid on Hepatocarcinogenesis in F344 Rats

Cited by 7 publications

References 34 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

Induction of Hepatocellular Proliferative Lesions in CBA Mice by a 26-week Dietary Administration of Kojic Acid

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