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

Abstract

-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.

Design, synthesis and in vivo/in vitro screening of novel chlorokojic acid derivatives

“…Moreover, these hydroxypyrone derivatives are known as effective chelating agents forming complexes with metals 5,12,13 and this ability plays a significant role in antimicrobial activity 14 . Kojic acid and its derivatives also display a variety of biological activities, such as antiepileptic 4,[6][7][8][9] , modest anti-inflammatory agent 5 , food additive 15 , antioxidant or antibrowning agent 16 , skinlightening product in cosmetics as a result of inhibition of melanin production 17 , herbicidal 18 , anti-speck 19 , pesticide and insecticide 20 , antitumor activity 21 and anti-diabetic agent 22 . Epilepsy, one of the more common neurological disorders, affects a large section of people.…”

Novel kojic acid-polymer-based magnetic nanocomposites for medical applications

“…28,29 KA 30 and its derivatives have been used in a variety of medical, food, agricultural, and industrial applications, such as an antibrowning agent (antispeck) and antioxidant; [31][32][33] for skin care, antiacne, and cosmetic applications due to its potent skin lightening/depigmenting properties, [34][35][36][37] and used for herbicide, insecticide, pesticide, [38][39][40][41] antidiabetic, 42 antitumor, 43 antiproliferative, 44 anticonvulsant, 31 and antimicrobial (including both antibacterial and antifungal) activities. 29,[45][46][47][48] In addition, it has also been shown that KA significantly enhances neutrophil phagocytosis and lymphocyte proliferation.…”

Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in an Ultra-Short-Term Skin Carcinogenesis Bioassay Using rasH2 Mice

“…It has been previously reported that skin nodules developed in CD-1 (ICR) mice treated with DMBA. 4,5 In that bioassay, TPA was applied at 4 mg/200 mL twice a week for 19 weeks, and the multiplicity ranged from 12 to 28. 4,5,21 In the present study, DMBA used as initiator was applied to back skin at a dose of 50 mg/100 mL acetone, and this dose was half that used in the 2-stage skin carcinogenesis bioassay with CD-1 (ICR) mice.…”